Systems and methods for generating nitric oxide

ABSTRACT

Systems and methods for nitric oxide generation are provided. In an embodiment, an NO generation system comprises a controller and disposable cartridge that can provide nitric oxide to two different treatments simultaneously. The disposable cartridge has multiple purposes including preparing incoming gases for exposure to the NO generation process, scrubbing exhaust gases for unwanted materials, characterizing the patient inspiratory flow, and removing moisture from sample gases collected. Plasma generation can be done within the cartridge or within the controller. The system has the capability of calibrating NO and NO2 gas analysis sensors without the use of a calibration gas.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication No. 62/463,943 filed Feb. 27, 2017, U.S. ProvisionalApplication No. 62/463,956 filed Feb. 27, 2017, U.S. ProvisionalApplication No. 62/509,394 filed May 22, 2017, U.S. ProvisionalApplication No. 62/553,572 filed Sep. 1, 2017, U.S. ProvisionalApplication No. 62/574,173 filed Oct. 18, 2017, and U.S. ProvisionalApplication No. 62/614,492 filed Jan. 7, 2018, and the contents of eachof these applications are hereby incorporated herein by reference intheir entireties.

FIELD

The present disclosure relates to systems and methods for generatingnitric oxide for use with a ventilation device.

BACKGROUND

Nitric oxide has found to be useful in a number of ways for treatment ofdisease, particularly cardiac and respiratory ailments. Previous systemsfor producing NO and delivering the NO gas to a patient have a number ofdisadvantages. For example, tank-based systems required large tanks ofNO gas at a high concentration and pressure. When treatment using thissystem is paused, NO in the circuit stalls and converts into NO₂,requiring the user to purge the manual ventilation circuit beforeresuming manual ventilation. Synthesizing NO from NO₂ or N₂O₄ requiresthe handling of toxic chemicals. Prior electric generation systemsinvolve generating plasma in the main flow of air to be delivered topatients, or pumped through a delivery tube.

Calibration of current systems can also be difficult, as a user isrequired to connect high pressure gas canisters containing calibrationgas to the system. Calibration gases typically include NO, NO₂, and O₂.For one concentration and one gas at a time, gas is flowed through thesensor chamber to provide a known input. This manual calibration cantake roughly 15 minutes or more of trained personnel time. Whentank-based systems flow, they release high-concentration (approximately800 ppm) NO into the ventilation system. When treatment with atank-based system is paused, NO in the manual circuit (Ambu-bag orequivalent) stalls and converts into NO, requiring the user to purge themanual ventilation device circuit before resuming manual ventilation.

SUMMARY

The present disclosure is directed to systems, methods and devices fornitric oxide generation for use with various ventilation devices. Insome embodiments, a nitric oxide generation system comprises one or moreplasma chambers each including one or more electrodes configured togenerate a product gas containing nitric oxide using a flow of areactant gas through the one or more plasma chambers. A controller isconfigured to regulate the amount of nitric oxide generated in theproduct gas by the one or more electrodes in the one or more plasmachambers using one or more parameters as input to a control algorithm,and at least one of the one or more parameters being related to the flowrate of the reactant gas into the one or more plasma chambers. Areactant gas source is configured to provide instantaneous high pressurereactant gas to the one or more plasma chambers. A flow controller ispositioned between the reactant gas source and the one or more plasmachambers and configured to provide a controlled continuous variable flowof the reactant gas from the reactant gas source based on a measurementassociated with a medical gas into which the product gas flows. One ormore scavenger paths configured to remove NO₂ from the product gasgenerated by the one or more plasma chambers. The concentration of NO inthe combined product gas and medical gas is a target value.

In some embodiments, the measurement associated with the medical gas isthe flow rate of the medial gas such that the air flow of the reactantgas through the one or more plasma chambers is proportional to the flowrate of the medical gas.

In some embodiments, the reactant gas source is in the form of areservoir. In some embodiments, the reactant gas source is in the formof a pump. In some embodiments, the flow controller is selected from thegroup consisting of one or more proportional valves, one or more digitalvalves, and a combination of at least one proportional valve and atleast one digital valves. In some embodiments, the system also includesone or more filters positioned to receive NO-enriched air from the oneor more scavenger paths and configured to filter the NO-enriched air. Insome embodiments, the system also includes a digital signal processorthat generates a continuous, customizable control AC waveform as aninput to a high voltage circuit. The digital signal processor isconfigured to control the shape of the AC waveform by controlling itsfrequency and duty cycle.

In some embodiments, a nitric oxide generation system comprises one ormore plasma chambers each including one or more electrodes configured togenerate a product gas containing nitric oxide using a flow of areactant gas through the one or more plasma chambers. A controller isconfigured to regulate the amount of nitric oxide generated in theproduct gas by the one or more electrodes in the one or more plasmachambers using one or more parameters as input to a control algorithm,and at least one of the one or more parameters being related to the flowrate of the reactant gas into the one or more plasma chambers. Areactant gas source is configured to provide instantaneous high pressurereactant gas to the one or more plasma chambers. A flow controller ispositioned between the reactant gas source and the one or more plasmachambers and configured to provide a controlled continuous variable flowof the reactant gas from the reactant gas source based on a measurementassociated with a medical gas into which the product gas flows. Theconcentration of NO in the combined product gas and medical gas is atarget value.

In some embodiments, the system also includes one or more scavengerpaths configured to remove NO₂ from the product gas generated by the oneor more plasma chambers. In some embodiments, the reactant gas source isin the form of a reservoir. In some embodiments, the reactant gas sourceis in the form of a pump.

In some embodiments, a nitric oxide generation system comprises one ormore plasma chambers each including one or more electrodes configured togenerate a product gas containing nitric oxide using a flow of areactant gas through the one or more plasma chambers. A controller isconfigured to control the amount of nitric oxide generated in theproduct gas by the one or more electrodes in the one or more plasmachambers based on a control algorithm with one or more input parametersby varying at least one or more of the flow rate of the reactant gasinto the one or more plasma chambers and a plasma power in the one ormore plasma chambers. A reactant gas source is configured to provideinstantaneous high pressure reactant gas to the one or more plasmachambers. A flow controller is positioned between the reactant gassource and the one or more plasma chambers and configured to provide acontrolled continuous variable flow of the reactant gas from thereactant gas source based on a measurement associated with a medical gasinto which the product gas flows. The concentration of NO in thecombined product gas and medical gas is a target value.

In some embodiments, the control algorithm input parameters are selectedfrom the group consisting of concomitant treatment parameters, patientparameters, ambient environment parameters, device parameters, and NOtreatment parameters. In some embodiments, the concomitant treatmentparameters include flow, pressure, gas temperature, gas humidityinformation relating to one or more device being used in conjunctionwith the NO generation system. In some embodiments, the patientparameters include inspiratory flow, SpO₂, breath detection, tidalvolume, minute volume, or expiratory NO₂. In some embodiments, theambient environment parameters include ambient temperature, ambientpressure, ambient humidity, ambient NO, or ambient NO₂. In someembodiments, the device parameters include plasma chamber pressure,plasma chamber flow, plasma chamber temperature, plasma chamberhumidity, electrode temperature, electrode type, or electrode gap. Insome embodiments, the NO treatment parameters include target NOconcentration, indicated NO concentration, or indicated NO₂concentration.

In some embodiments, the system also includes one or more scavengerpaths configured to remove NO₂ from the product gas generated by the oneor more plasma chambers. In some embodiments, the reactant gas source isin the form of a reservoir.

A method for generating NO in a product gas is also provided, andincludes generating a product gas using one or more plasma chambers eachincluding one or more electrodes containing nitric oxide using a flow ofa reactant gas through the one or more plasma chambers, and regulatingthe amount of NO generated in the product gas using a controller inconjunction with the one or more electrodes in the one or more plasmachambers by using one or more parameters as input to a controlalgorithm. At least one of the one or more parameters is related to theflow rate of the reactant gas into the one or more plasma chambers. Themethod also includes providing instantaneous high pressure reactant gasto the one or more plasma chambers from a reactant gas source. Themethod also includes providing a controlled continuous variable flow ofthe reactant gas from the reactant gas source based on a measurementassociated with a medical gas into which the product gas flows using aflow controller that is positioned between the reactant gas source andthe one or more plasma chambers. One or more scavenger paths removes NO₂from the product gas generated by the one or more plasma chambers. Theconcentration of NO in the combined product gas and medical gas is atarget value.

In some embodiments, a system for generating nitric oxide is providedthat comprises a cartridge configured to produce nitric oxide to bedelivered through a respiratory gas delivery device. The cartridgeincludes an inlet for receiving reactant gas, one or more plasmachambers configured to produce nitric oxide from the reactant gas, andan outlet for delivering the nitric oxide to the respiratory gasdelivery device. A controller is configured to receive feedback from thecartridge to allow the controller to regulate the production of nitricoxide by the cartridge by adjusting the flow rate of the plasma chambergas and a duration or intensity of plasma activity in the plasmachamber. In some embodiments, the cartridge does not include a plasmachamber.

In some embodiments, the cartridge can also include one or morescavengers coupled between the one or more plasma chambers and theoutlet, and the one or more scavengers (scrubbers) can be configured toremove NO₂ from the generated nitric oxide. The one or more scavengerscan be the same length, or different lengths. Different lengths can bedesirable when the purpose of each scavenger differs. Differingapplications can include neonate ventilation, adult ventilation, facemask treatment and manual respiration with a bag. In some embodiments,the cartridge is a calibration cartridge that directs known amounts ofNO and NO₂ output to one or more sensors. In an embodiment, the reactantgas is atmospheric air.

In some embodiments, the controller can also include one or more sensorsconfigured to sense the nitric oxide concentration in the cartridgeand/or patient inspiratory circuit such that the nitric oxide productioncan be adjusted based on feedback from the one or more sensors. In anembodiment, the controller is configured to control the duty cycle ofplasma activity in a first plasma chamber at a first duty cycle to allowfor the delivery of nitric oxide and to control the duty cycle of plasmaactivity in a second plasma chamber at a second duty cycle. The secondduty cycle is less than the first duty cycle such that the plasmaactivity in the second plasma chamber is used to check the viability ofthe second plasma chamber as a backup plasma chamber to the first plasmachamber. In some embodiments, a first plasma chamber and a second plasmachamber are used in an alternating fashion to even the wear on bothwhile still retaining a viable back-up.

In some embodiments, the one or more plasma chambers allow forsimultaneous delivery of nitric oxide to one or more ventilationdevices. The one or more ventilation devices can include an automaticventilation device and a manual ventilation device. In an embodiment,the one or more plasma chambers allows for redundancy to allow forcontinuous nitric oxide delivery in the event of a fault in one of theone or more plasma chambers. In some embodiments, both plasma chambersare used in unison to deliver a maximum dose of NO. In some embodiments,one plasma chamber is used to deliver NO to a patient while the otherplasma chamber delivers NO to a sensor bank to confirm functionality.

In some embodiments, a system for generating nitric oxide is providedthat comprises a cartridge configured to deliver nitric oxide to bedelivered through a respiratory gas delivery device. The cartridgeincludes an inlet for receiving reactant gas and an outlet fordelivering the nitric oxide to the respiratory gas delivery device. Acontroller includes one or more plasma chambers configured to producenitric oxide from the reactant gas. The controller is configured toreceive control input from the cartridge to allow the controller toregulate the production of nitric oxide by adjusting the flow rate ofthe plasma chamber gas and a duration of plasma activity in the plasmachamber. In an embodiment, the control input is in the form of a flowmeasurement of inspiratory gases in the cartridge. In anotherembodiment, the control input is in the form of a pressure measurementof inspiratory gases in the cartridge.

In some embodiments, the cartridge is a self-test (calibration)cartridge that is configured to direct flow from the plasma chamber tosystem gas analysis sensors in the controller. In some embodiments, thecartridge is a scavenger cartridge that includes one or more scavengersconfigured to remove NO₂ from the generated nitric oxide. The one ormore scavengers can be oriented in a vertical plane with atwo-dimensional switchback or maze configuration. This approach providesa benefit in that product gases plunge down into pockets of scavengermaterial, ensuring that all gas comes into contact with scavengermaterial.

In some embodiments, the controller is configured to communicate withthe cartridge such that the controller can access information relatingto the cartridge, the information being an expiration date of thecartridge or cartridge type or unique ID. The controller can utilize theinformation from the cartridge related to cartridge type to control NOproduction.

In some embodiments, an NO generation system can vary the flow rate ofair through the plasma chamber. In an embodiment, an NO generationsystem can use an air pump to pull NO₂-contaminated air away from thepatient to clean the lines. In some embodiments, an NO generation systemuses oxygen concentrator membrane technology to increase the O₂ contentof gas in the plasma chamber thereby increasing the NO productionefficiency. In some embodiments, an NO generation system can use oxygenconcentrator technology to reduce O₂ concentration in the NO-containingpost-plasma gas stream to reduce the NO₂ formation rate. In someembodiments, an NO generation system has an inspiratory flow IN and anInspiratory flow OUT connection, but does not generate NO within theinspiratory flow. In an embodiment, an NO generation system can supporttwo or more independent NO treatments at once, for example a ventilatorcircuit and a manual ventilation device.

In some embodiments, an NO generation system continues NO generationdespite any alarm. In some embodiments, an NO generation system includesa watchdog circuit that monitors plasma activity and can switch plasmaactivity from one plasma chamber to another plasma chamber.

In some embodiments, an NO generation system includes wirelesscommunication capability that enables two controllers to communicate,for example, directly, in order to transfer treatment and systeminformation from one controller to the other. In another embodiment, NOgeneration systems can communicate indirectly through the internet or acloud network to transfer information.

In some embodiments, an NO generation system uses one or more ofinspiratory air flow, inspiratory air pressure, inspiratory airhumidity, ambient temperature, ambient pressure, plasma chamberpressure, and/or humidity as inputs into the plasma control algorithm.In an embodiment, an NO generation system uses pulse width modulation ofa resonating circuit to vary NO production. In some embodiments, the NOgeneration system modulates air flow and a plasma parameter (forexample, pulse duty cycle, pulse frequency, or, burst duty cycle, burstfrequency, burst duration, and/or pulse power) to maintain a constantconcentration of NO leaving the plasma chamber. In some embodiments, theNO generation system modulates air flow and a plasma parameter (pulsewidth, frequency, or power) to maintain a constant concentration of NOin the main airflow to a patient (ventilator air stream, for example).

In some embodiments, an NO generation system uses gas output of theplasma chamber to self-check that NO and NO₂ are being generated. Insome embodiments, an NO generation system includes a self-test(calibration) cartridge that, when inserted, either enables or initiatesa self-calibration process for NO and NO₂ sensors. In some embodiments,the calibration cartridge can shunt flow from the calibration cartridgeto the gas sensors. In some embodiments, an NO generation systemincludes an integrated calibration pathway for self-calibration ofsensors.

In some embodiments, an NO generation system has a mode that checks theexpiration date (shelf life) of a cartridge prior to permitting clinicaluse, or can check whether or not a cartridge has been inserted into asystem previously. In some embodiments, an NO generation system canenter a cartridge check mode upon start-up, when a cartridge is removed,and when the system wakes from a sleep mode.

In some embodiments, users want to be able to direct NO to more than onetreatment at a time from the same system, for example: simultaneousmanual and automatic ventilation. In order to support both modessimultaneously with different flow rates and NO concentrations, in someembodiments there is an NO generation system disposable cartridge withmore than one scavenger path. A system that includes redundant scavengerpaths allows the system to support a plurality of different treatmentmethods at different NO concentrations.

In an embodiment, an NO₂ scavenger comprised of particles of soda limematerial. This material is brittle and can fracture during transit, thusa physical filter (not to be confused with the chemical scavenger) isrequired to remove scavenger particulate from the air stream. In anembodiment shown in FIG. 86, the scavenger path has multiple particlefilters spaced along the flow path to capture soda lime particles. Thisdesign limits the amount of particles that can collect in any onefilter.

When a disposable cartridge is packaged and shipped to the customer,there is a risk that vibrations during transit could make the scavengermaterial settle, generating gas pathways through the cartridge that donot require contact with scavenger material. In some embodiments, thegas can make contact with scavenger material after vibration and/or whenthe cartridge is tilted with respect to vertical. In some embodiments,the gas can flow through the scavenger material after vibrations fromtransit.

In an embodiment, a cartridge can have a reusable housing that enables auser to replace scavenger material only. In an embodiment, a cartridgecan include one or more outlet valves to prevent back flow from thepatient inspiratory flow into the cartridge.

In an embodiment, an NO generation system includes composite electrodescomprised of a low-cost material connected to a noble metal/alloy pad.In an embodiment, an NO generation system can be used that includes anarray of electrode pairs that are used one at a time for the purposes ofprolonging the mean time between services. In an embodiment, electrodesmay be exhausted in series or may be used in a cyclic pattern to evenwear and reduce temperatures.

There are various ways to control the NO production. In someembodiments, an NO generation system can be used that determines plasmaparameters by using a look up table with one or more of the followinginputs: target inhaled NO concentration, cartridge type, inspired airflow rate, inspired air temperature, inspired air humidity, inspired airpressure, ambient temperature, plasma chamber pressure, plasma chambergas flow rate, ambient pressure, ambient humidity, air reservoirpressure, inspired O₂ measured, inspired O₂ limits, reactant gas O₂level and measured NO values in the ventilator inspiratory line. In someembodiments, an NO production system can be used that pulls in ambientair, pumps said air through a plasma, scavenges and filters said airprior to merging it with a secondary flow of air to a patient. In anembodiment, an NO generation system can be used that uses pumps thatblock flow when off to prevent creating a leak in the patientinspiratory flow. In some embodiments, an NO generation system can beused that uses a valve to block flow when NO generation is off toprevent creating a leak in the patient inspiratory flow.

In an embodiment, an NO generation system pulls in ambient air, pumpssaid air through a plasma, scavenges and filters said air prior tomerging it with a secondary flow of air to a patient. In one embodiment,NO-containing air is filters before and after the scavenger.

In an embodiment, an NO generation system can, upon completion ofpatient manual ventilation, turn off the plasma but continue running thegas pump for a set time or pump rotations to purge the manualventilation device of one or more of NO and NO₂. In another embodiment,the system can suck out the line to clear the line away from thepatient. The time and/or pump rotations are determined based on thevolume of air required to be moved to clean out the ventilator circuitof NO. Thus, air can be pumped without NO generation and air can bepumped before stopping the pump whenever treatment is stopped or paused.In an embodiment, the pump can continue to run until one or more of NOand NO₂ levels indicated by respective sensors are at acceptable levels.

In an embodiment, an NO generation system is provided that generates aplasma within a patient inspiratory air stream. The device measures O₂levels within the inspiratory air and varies plasma parametersaccordingly to maintain a particular NO concentration profile within theinspired air. In an embodiment, an NO generation system with replaceableelectrodes is provided that can be used for multiple patients.

In an embodiment, an NO generation system is provided with one or moreremovable cartridges containing one or more of the following features: ahousing, an incoming plasma air filter, ventilator flow inlet,ventilator flow conduit, ventilator flow outlet, incoming air scavengermaterial, enclosure air filter, plasma chamber, electrode assembly(s),an air pump, ventilator flow measurement, a manual ventilation deviceflow inlet, a manual ventilation device flow outlet, manual ventilationcircuit flow measurement, a manual/backup selector, a sample lineconnection, a water trap, a water trap drain, dual NO₂ scavenger paths,outlet check valves, outlet filters and a memory device.

In an embodiment, an NO generation system is provided that includesredundant plasma generation that periodically checks the viability ofthe back-up plasma generator. In an embodiment, an NO generation systemis provided with an electrode assembly comprised of an electrode pair, aheat sink, and a gas passageway. The electrode assembly can have a gaspassageway consisting of a blind hole (a single opening for gasintroduction and removal). In some embodiment, an electrode assembly isconfigured as a Faraday-cage assembly with adequate air flow to reducethe broad-band emissions generated by the HV electrode assembly.

In an embodiment, an NO generation system with disposable cartridge withwater-trap of volume greater than 20 ml (for example, 60 ml) isprovided. In an embodiment, a disposable water trap withsyringe-actuated valve for drainage is provided.

Relating to NO production control, in some embodiments, reactant gasflow rate and spark frequency are controlled. In an embodiment, reactantgas flow rate and spark duty cycle are controlled. In an embodiment, airflow rate is varied linearly with respiratory flow rate variation withbreath. In an embodiment, plasma pulse rate can be varied as well tomaintain constant NO concentration throughout the respiratory cycle. Inan embodiment, air pump speed is held constant and only plasma controlparameters (B=spark groups per second, P=time between discharges,N=number of discharges per group, and H=pulse time) are varied toproduce required NO concentrations based on patient inspiratory flow.

In an embodiment, an NO generation system includes a mode that inspectsa cartridge for proper function (spark, patency) and expiration dateprior to permitting treatment. In an embodiment, an NO generation systemcan enter a demonstration mode when a training cartridge is inserted.

In an embodiment, an NO generation system uses NO₂ measurements as asubstitute for NO measurements in the event of an NO sensor failurebased on a known relationship between NO and NO₂ production. Forexample, for a system that generates NO₂ concentrations at 10% of NOconcentrations, the system can only measure NO₂ and infer that NO levelsare approximately 10× greater or more. The term “or more” is usedbecause it takes time for inspiratory gases to travel from the samplecollection location to the gas sensors. During that transit time, NO canoxidize to NO₂, making the indicated NO₂ reading higher than the levelof NO₂ at the sample collection location.

When the NO delivery system is delivering NO to a ventilator circuit orother pulsatile air flow, the flow of air through the plasma chamber canvary. Often, the plasma chamber flow is controlled to vary in proportionto the ventilator circuit flow. Some ventilator circuit flows have zerobias flow, i.e. the flow in the circuit is zero between the end of oneinspiratory period and the beginning of the subsequent inspiratoryperiod. In this situation, a proportional NO flow would have zero flowduring exhalation. Even if the plasma activity is stopped during periodsof zero or very low ventilator flow, latent NO in and downstream fromthe plasma chamber will convert to NO₂ between patient breaths. In thisscenario, it is beneficial to maintain a trivial amount of flow throughthe plasma chamber to flush remaining NO out of the system into theventilator stream. The low flow may be generated by running a pump at alow speed, having a bleed hole in a valve before the plasma chamber sothat it is never completely obstructs flow, having a side stream airpath that is always open in parallel to a flow controller, having a flowproportional valve that never closes to zero opening, or other means.Without one or more of these mitigations to flush latent NO from theplasma chamber, NO₂ concentration may increase in the main air streamwhen ventilator flow, and NO delivery resume.

In an embodiment, the electrodes are located in a controller of thedevice rather than in a disposable cartridge. This allows the plastic ofthe cartridge to be positioned at a distance from the heat of theelectrodes, a reduced cost of the cartridge, and increased distancesfrom the user high voltage. It can also improve electro-magneticinterference (EMI) shielding, allow for the ability to self-calibratethe device using the controller without a calibration cartridge, and caneliminate a high voltage connection to the disposable cartridge.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure is further described in the detailed descriptionwhich follows, in reference to the noted plurality of drawings by way ofnon-limiting examples of exemplary embodiments, in which like referencenumerals represent similar parts throughout the several views of thedrawings, and wherein:

FIG. 1 is an exemplary embodiment of a system for generating anNO-enriched product gas;

FIG. 2 is an exemplary embodiment of an NO generation system;

FIG. 3 is an exemplary embodiment of an NO generation system;

FIG. 4A is an exemplary embodiment of an inline nitric oxide generationsystem;

FIG. 4B is an exemplary embodiment of a sidestream nitric oxidegeneration system;

FIG. 4C is an exemplary embodiment of a mainstream nitric oxidegeneration system;

FIG. 5A is an exemplary embodiment of an inline nitric oxide generationsystem;

FIG. 5B is an exemplary embodiment of a mainstream nitric oxidegeneration system;

FIG. 6 is an exemplary embodiment of a controller of a nitric oxidegeneration system that includes more than one flow circuit;

FIG. 7 is a flowchart of an embodiment of plasma generation that sourcesambient air separate from a main gas stream;

FIG. 8 is a flowchart of an embodiment of plasma generation withredundant plasma generators and scavengers;

FIG. 9 is an embodiment of a sample line;

FIG. 10 is an embodiment of an injection end of a sample line;

FIG. 11 is an exemplary embodiment of a mainstream NO generation systemthat can be used with a manual ventilation device;

FIG. 12A and FIG. 12B are embodiments of manual ventilation devices foruse with an NO generation device;

FIG. 13A and FIG. 13B are embodiments of manual ventilation devices foruse with an NO generation device;

FIG. 14 is an embodiment of manual ventilation device for use with an NOgeneration device;

FIG. 15 is an exemplary embodiment of a NO generation system thatincludes a disposable cartridge and a controller;

FIG. 16A and FIG. 16B illustrates exemplary plasma NO generating pulsesfor electrode assemblies in normal and failure states;

FIG. 17A is an embodiment of an NO generation system with one or moreplasma chambers located within a cartridge;

FIG. 17B is an embodiment of an NO generation system with one or moreplasma chambers located within a controller;

FIG. 18 illustrates an embodiment of a schematic of a controller of anNO generation system;

FIGS. 19, 20, 21, 22, 23, 24, and 25 are embodiments of mechanisms forcreating a pulsatile air flow;

FIGS. 26A, 26B, and 26C are embodiments of flow sources and plasmachambers;

FIG. 27 is a plasma generation circuit including a waveform controlcircuit and a high voltage circuit;

FIG. 28 is an exemplary embodiment of a high voltage trigger circuit;

FIG. 29 is exemplary waveform generated by a high voltage controller DSPprocessor;

FIG. 30 illustrates an exemplary electrode manifold;

FIG. 31A is an exemplary embodiment of an electrode assembly withindependent entry and exit points;

FIG. 31B is a cross-sectional view of the electrode assembly of FIG.31A;

FIG. 31C is a side view of the electrode assembly of FIG. 31A;

FIG. 32A and FIG. 32B illustrate an exemplary embodiment of an electrodeassembly with a blind hole for gas flow;

FIG. 33 is an exemplary embodiment of an electrode assembly mounted to acontroller;

FIG. 34 is an embodiment of an electrode assembly for generating NO inan NO generation system

FIG. 35 is an embodiment of an electrode assembly for generating NO inan NO generation system;

FIG. 36 is an embodiment of an electrode assembly for generating NO inan NO generation system;

FIG. 37 illustrates various embodiments of electrodes with features forbottoming out;

FIG. 38 is an embodiment of an electrode assembly that allows for airflow across an electrode gap;

FIG. 39 is an embodiment of an electrode assembly;

FIG. 40 is an exemplary graph of a spark frequency resonance scan fordetermining a resonant frequency for a high voltage circuit;

FIG. 41 is an exemplary graph for determining noise in a high voltagecircuit to detect plasma;

FIG. 42 is an embodiment of an electrode assembly having an o-ring;

FIG. 43 is an embodiment of an electrode assembly;

FIGS. 44A, 44B and 44C are embodiments of an electrode assembly;

FIG. 45 is an embodiment of an electrode assembly;

FIG. 46A is an embodiment of an electrode assembly;

FIG. 46B is an embodiment of an electrode assembly;

FIG. 47A and FIG. 47B illustrate a back and side view of an embodimentof a controller enclosure;

FIG. 48 is an exemplary graph depicting elapsed time versus NO settings;

FIG. 49 is a schematic of an embodiment of a cartridge for use with anNO generation system;

FIG. 50 is an embodiment of an NO generation system with a visual alarmstatus component;

FIG. 51A, FIG. 51B, FIG. 51C, FIG. 51D, FIG. 51E, FIG. 51F, and FIG. 51Gare embodiments of a user interface for displaying information relatedto NO production to a user;

FIG. 52, FIG. 53, FIG. 54, FIG. 55, FIG. 56, FIG. 57, FIG. 58, FIG. 59,FIG. 60, FIG. 61, and FIG. 62 are embodiments of a user interface of anNO generation system;

FIG. 63 is an embodiment of a scavenger path;

FIG. 64 is an embodiment of a cartridge housing with multiple cylinderstherein for managing scavenger tubes;

FIGS. 65-68 are embodiments of pneumatic circuits;

FIG. 69 illustrates an embodiment of recirculation of NO;

FIG. 70 is an embodiment of a recirculating loop that continuouslyremoves NO₂ from stores NO-containing gas;

FIG. 71 is an embodiment of a system where recirculated gas flows backthrough the NO generator;

FIG. 72 is an embodiment of a calibration cartridge;

FIG. 73 is an embodiment of a sensor pack having a water trap;

FIG. 74 is an embodiment of a Faraday cage plasma chamber;

FIG. 75 is an embodiment of a solid metal plasma chamber;

FIG. 76 is an embodiment of an NO generation system with a ventcartridge and a scavenger cartridge;

FIG. 77 is an embodiment of a vent cartridge;

FIG. 78 is an embodiment of a vent cartridge;

FIG. 79 is an embodiment of a scavenger cartridge;

FIG. 80 is a flowchart of an exemplary embodiment of software modes ofan NO generation system;

FIG. 81 is a flowchart of another exemplary embodiment of software modesof an NO generation system;

FIG. 82 is an embodiment of a user interface for displaying informationrelated to alarm history;

FIG. 83 is another embodiment of an NO generation system with a visualalarm status component;

FIG. 84 is an embodiment of an NO generation system;

FIG. 85 is an embodiment of a piston-pump configuration;

FIG. 86 is an exemplary graph comparing ventilator flow and injectionflow using a piston-pump configuration;

FIG. 87 is an exemplary graph of NO concentration over time when asingle-acting piston is used;

FIG. 88 is an embodiment of an NO generation system using at least onereservoir;

FIG. 89 is an exemplary graph comparing ventilator flow, plasma airflow, and NO levels;

FIG. 90 is an embodiment of an NO generation system using at least onereservoir;

FIG. 91 is an embodiment of an NO generation system having dual-flowpaths;

FIG. 92 is an embodiment of an NO generation system having a single pumpand flow path;

FIG. 93 is an embodiment of an NO generation system having a flow pathwith a pump and a flow director;

FIG. 94 is an embodiment of an NO generation system that varies air flowthrough the system;

FIG. 95 is an embodiment of an NO generation system that utilizes aplurality of controllers to control flow through the system;

FIG. 96 is an embodiment of an NO generation system that utilizes morethan one air source;

FIG. 97 is an embodiment of an NO generation system that utilizes a dosecontroller to control a plurality of air sources;

FIG. 98 is an embodiment of system for generating NO;

FIG. 99 is an embodiment of a sensor pack having a water trap and apump;

FIG. 100 is an embodiment of a nasal cannula prong design for use withan NO generation system;

FIG. 101 is an embodiment of a cannula and tubing with a perforated airlumen;

FIG. 102 is an embodiment of a cannula and tubing with a perforated airlumen;

FIG. 103 is an embodiment of an ambulatory NO generation device;

FIG. 104 is an embodiment of a cannula and tubing with a perforated airlumen and scavenger;

FIG. 105 are multiple view of embodiment of an ambulatory NO generationdevice;

FIGS. 106A and 106B illustrate embodiments of an NO generation devicewith a scavenger cartridge located at side and bottom of the device,respectively;

FIGS. 107A and 107B illustrate embodiments of an NO generation devicewith a user interface and a scavenger cartridge on side surfaces of thedevice;

FIG. 108 is an embodiment of an ambulatory NO generation device;

FIG. 109 is an embodiment of an ambulatory NO generation device;

FIG. 110 is an embodiment of an ambulatory NO generation device;

FIG. 111 is an embodiment of an ambulatory NO generation system;

FIG. 112 is an embodiment of an ambulatory NO generation system;

FIG. 113 is an embodiment of an NO generation system with redundancy;

FIG. 114 is an exemplary embodiment of a nitric oxide generation modulefor use with a ventilator;

FIG. 115 is an exemplary embodiment of an NO generation module and asensor module that are configured to be removably coupled to respiratoryequipment;

FIG. 116 is an exemplary embodiment of an NO generation module forgenerating NO;

FIG. 117 is an exemplary embodiment of an NO generation module removablycoupled to a ventilator;

FIG. 118 is an exemplary embodiment of an NO generation module embeddedin a ventilator;

FIG. 119 is an exemplary embodiment of an NO generation module removablycoupled to a ventilator;

FIG. 120 is another exemplary embodiment of an NO generation modulecoupled to a ventilator pre-ventilation that utilizes ambient air for NOgeneration;

FIG. 121 is an exemplary embodiment of an NO generation module coupledto a ventilator with an air outlet from the module to the ventilator;

FIG. 122 is an exemplary embodiment of an NO generation module coupledto a ventilator;

FIG. 123 is an exemplary embodiment of an NO generation module with ananaesthesia machine;

FIG. 124 is an exemplary embodiment of an NO generation module with acontinuous positive airway pressure (C-PAP) machine;

FIG. 125 is an exemplary embodiment of an NO generation module with aC-PAP machine;

FIG. 126 depicts various embodiments of NO generation modules in usewith O₂ sources;

FIG. 127 is an exemplary Oxygen concentrator with embedded NO module;

FIG. 128 is an exemplary embodiment of an NO generation module with anextracorporeal membrane oxygenator (ECMO) system;

FIG. 129 is an exemplary embodiment of a sensor module;

FIG. 130 is an exemplary embodiment of a perspective view of thecomponents inside a sensor module;

FIG. 131 is an exemplary removable NO generation module that acceptscompressed air;

FIG. 132 is an exemplary removable combination NO module and GasAnalysis module;

FIG. 133 is an exemplary embodiment of a patient monitor coupled to anNO generation module;

FIG. 134 is an exemplary embodiment of a patient monitor coupled to anNO generation module;

FIG. 135 is an exemplary embodiment of a patient monitor and NOgeneration module for use in a catheterization laboratory.

FIG. 136 is an exemplary embodiment of an electric NO generation tankreplacement device;

FIG. 137 is an exemplary embodiment of internal components of the deviceof FIG. 136;

FIG. 138 is an exemplary embodiment of an electric NO generation tankreplacement device with a pressurized gas source;

FIG. 139 is an exemplary embodiment of an electric NO generation tankreplacement device with a remote output;

FIG. 140 is an exemplary embodiment of a combined scavenger and airfilter;

FIG. 141 is an exemplary embodiment of an electric NO generation tankreplacement device with a single lumen output;

FIG. 142 is an exemplary embodiment of an electric NO generation tankreplacement device with a remote flow sensor;

FIG. 143 depicts an embodiment of a hardware architecture of an NOgeneration and delivery system with redundancy; and

FIG. 144 is an embodiment of a Generate and Delivery NO (GDN) board.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION

The following description provides exemplary embodiments only, and isnot intended to limit the scope, applicability, or configuration of thedisclosure. Rather, the following description of the exemplaryembodiments will provide those skilled in the art with an enablingdescription for implementing one or more exemplary embodiments. It willbe understood that various changes may be made in the function andarrangement of elements without departing from the spirit and scope ofthe presently disclosed embodiments

Specific details are given in the following description to provide athorough understanding of the embodiments. However, it will beunderstood by one of ordinary skill in the art that the embodiments maybe practiced without these specific details. For example, systems,processes, and other elements in the presently disclosed embodiments maybe shown as components in block diagram form in order not to obscure theembodiments in unnecessary detail. In other instances, well-knownprocesses, structures, and techniques may be shown without unnecessarydetail in order to avoid obscuring the embodiments.

Also, it is noted that individual embodiments may be described as aprocess which is depicted as a flowchart, a flow diagram, a data flowdiagram, a structure diagram, or a block diagram. Although a flowchartmay describe the operations as a sequential process, many of theoperations can be performed in parallel or concurrently. In addition,the order of the operations may be re-arranged. A process may beterminated when its operations are completed, but could have additionalsteps not discussed or included in a figure. Furthermore, not alloperations in any particularly described process may occur in allembodiments. A process may correspond to a method, a function, aprocedure, a subroutine, a subprogram, etc. When a process correspondsto a function, its termination corresponds to a return of the functionto the calling function or the main function.

Subject matter will now be described more fully with reference to theaccompanying drawings, which form a part hereof, and which show, by wayof illustration, specific example aspects and embodiments of the presentdisclosure. Subject matter may, however, be embodied in a variety ofdifferent forms and, therefore, covered or claimed subject matter isintended to be construed as not being limited to any example embodimentsset forth herein; example embodiments are provided merely to beillustrative. The following detailed description is, therefore, notintended to be taken in a limiting sense.

In general, terminology may be understood at least in part from usage incontext. For example, terms, such as “and”, “or”, or “and/or,” as usedherein may include a variety of meanings that may depend at least inpart upon the context in which such terms are used. Typically, “or” ifused to associate a list, such as A, B, or C, is intended to mean A, B,and C, here used in the inclusive sense, as well as A, B, or C, hereused in the exclusive sense. In addition, the term “one or more” as usedherein, depending at least in part upon context, may be used to describeany feature, structure, or characteristic in a singular sense or may beused to describe combinations of features, structures or characteristicsin a plural sense. Similarly, terms, such as “a,” “an,” or “the,” again,may be understood to convey a singular usage or to convey a pluralusage, depending at least in part upon context. In addition, the term“based on” may be understood as not necessarily intended to convey anexclusive set of factors and may, instead, allow for existence ofadditional factors not necessarily expressly described, again, dependingat least in part on context.

The present disclosure related to systems and methods of nitric oxide(NO) delivery for use in various applications, for example, in ahospital setting. An NO generation and/or delivery system can take manyforms, including but not limited to a device configured to work with anexisting medical device that utilizes a product gas, a stand-alone(ambulatory) device, a module that can be integrated with an existingmedical device, one or more types of cartridges that can perform variousfunctions of the NO system, and an electronic NO tank. The NO generationsystem uses a reactant gas, including but not limited to ambient air, toproduce a product gas that is enriched with NO.

FIG. 1 illustrates an exemplary embodiment of an NO generation system 10that includes components for reactant gas intake 12 and delivery to aplasma chamber 22. The plasma chamber 22 includes one or more electrodes24 therein that are configured to produce, with the use of a highvoltage circuit 28, a product gas 32 containing a desired amount of NOfrom the reactant gas. The system includes a controller 30 in electricalcommunication with the high voltage circuit 28 and the electrodes 24that is configured to control the concentration of NO in the product gas32 using one or more control parameters relating to conditions withinthe system and/or conditions relating to a separate device fordelivering the product gas to a patient and/or conditions relating tothe patient receiving the product gas. The controller 30 is also incommunication with a user interface 26 that allows a user to interactwith the system, view information about the system and NO production,and control parameters related to NO production.

The density of ambient air varies significantly with altitude. Tosupport consistent operation at high altitudes or with changing ambientpressure, the pneumatic pathway can include one or more adjustablemembers (such as a needle valve, array of digital valves or proportionalvalve) whose purpose is to impose a flow restriction to raise theupstream pressure and density.

In some embodiments, the NO system pneumatic path includes a pumppushing air through a manifold 36. The manifold is configured withthree-way valves and proportional orifices. The high voltage controlcircuit 28 controls the flow of the pump, the power in the plasma andthe direction of the gas flow post-electrical discharge. By configuringvalves, the high voltage control circuit can direct gas to the manualrespiration pathway, the ventilator pathway or the gas sensor chamberfor direct measurement of NO, NO₂ and O₂ levels in the product gas.

The output from the NO generation system in the form of the product gas32 enriched with the NO produced in the plasma chamber 24 can either bedirected to a respiratory or other device for delivery to a patient, orcan be directed to a plurality of components provided for self-test orcalibration of the NO generation system. In some embodiments, the systemcollects gases to sample in two ways: 1) gases are collected from apatient inspiratory circuit near the patient and pass through a sampleline 48, a filter 50, and a water trap 52, or 2) gases are shunteddirectly from the pneumatic circuit as they exit plasma chamber. Inanother embodiment, product gases are shunted with a shunt valve 44 tothe gas sensors after being scrubbed but before dilution into a patientairstream. In another embodiment, product gases are collected from aninspiratory air stream near the device and/or within the devicepost-dilution. Within the gas analysis portion of the device, theproduct gas passes through one or more sensors to measureconcentrations, pressure, and flow rate of various gasses therein.

Another exemplary embodiment of an NO generation system 60 is shown inFIG. 2, which includes a scavenger cartridge 62, a ventilator cartridge64, a water trap 66, a disc filter 68, a sample line 70, and a T fitting72. Another exemplary embodiment of an NO generation system is shown inFIG. 3, which includes a carrying handle 80, an interface 82, a highvoltage cage 84, a control board 86, one or more cooling fans 88, and awater trap PCB 90. The system also includes an air pump 96, a highvoltage PCB 98, an upper manifold 100, a proportional valve 102, a DCpower entry 104, an HV transformer 106, an AC power entry 108, areservoir 110, and a flow director valve 112.

Delivery Types

Mechanical Ventilation

Nitric oxide in a product gas that is produced by an NO generationsystem can be delivered in a plurality of ways, for example, usingmechanical techniques, such as inline (FIG. 4A), sidestream (FIG. 4B),and mainstream (FIG. 4C) gas delivery. Within FIG. 4A, FIG. 4B, and FIG.4C, an NO generation device is coupled to a ventilator 122 to introduceNO-containing gas to a ventilator circuit. Inline delivery involvesgenerating a plasma within the main flow of gas to the patient (depictedas a green box within the inspiratory airstream). Sidestream delivery130 involves generating plasma in a small flow of gas, pumping thatNO-containing gas through a tube to a fitting on the main flow of gas tothe patient, as illustrated in FIG. 5A. Mainstream delivery 140 issimilar to sidestream production without the tube between a plasmasource and main flow of gas, as illustrated in FIG. 5B. For inlineproduction and delivery of the NO, the nitric oxide is generated withinthe main gas flow of an inspiratory limb of a ventilator circuit, or aninhaler. Complexities arise, however, in this configuration becausevarying levels of oxygen in the inspired gas affect oxygen-nitrogenratios, directly affecting the amount of nitric oxide generated for agiven duration and intensity of plasma. In a case where a patientreceives 100% oxygen, no NO could be formed due to the lack of nitrogen.Furthermore, the scavenger materials that clean NO₂ from the NO flowalso remove CO₂. Scavenging the main flow of air requires a largerscavenger that can absorb CO₂ from the entire patient air flow inaddition to NO₂. Another complexity with inline generation is that mostconfigurations require opening of the ventilator circuit to replacescavenger material.

In some embodiments, an electric nitric oxide generation system cangenerate the plasma using atmospheric air as the reactant gas, where theoxygen composition is approximately 21% of the atmospheric air byvolume. Two delivery schemes can be considered when generating nitricoxide from room air: sidestream (or off-line) and mainstream. In someembodiments of sidestream production, the plasma is generated within acontroller and then pumped via a tube to the inspiratory limb of aventilator circuit or other point of use. In some embodiments ofmainstream production, the inspiratory limb flow may be routed eitherpartially or in its entirety through the controller, thereby eliminatingthe need for a tube between controller and inspiratory limb.

Both sidestream and mainstream nitric oxide production within acontroller can have advantages over producing nitric oxide within theinspiratory limb of a ventilator circuit. For example, production withina controller eliminates the need for a high voltage connector and cablefrom controller to plasma chamber, thereby eliminating the potential fora user to come into contact with the high voltage electricity requiredto generate a plasma. Electromagnetic emissions can be reduced owing tothe lack of high voltage electrical cable that may emit electromagneticinterference during plasma generation. Generating plasma in atmosphericair can prolong electrode life because the oxygen concentration is lowerthan that which can be found in the inspiratory limb of a ventilator,where oxygen levels can reach up to 100%. The acoustic noise generatedfrom continuous and/or intermittent plasma generation can be controlledbetter when the plasma is generated within an enclosure, as provided bythe controller and/or disposable components. An oxygen sensor is notrequired in a system that generates plasma in atmospheric air. NOproduction levels vary with oxygen level, so an algorithm would berequired to generate specific amounts of NO in the absence of controlfeedback. Less scavenger material is required for a given scavengerservice life in systems that scavenge the sidestream NO-containing gasflow before it is blended with the inspiratory gas flow because thescavenger does not scavenge the entire gas flow to the patient.

FIG. 4A, FIG. 4B, and FIG. 4C illustrate various configurations ofnitric oxide generation systems for a ventilator or anesthesia circuit.FIG. 4A depicts an embodiment of an inline view 120, FIG. 4B depicts anembodiment of a sidestream view 124, and FIG. 4C depicts an embodimentof a mainstream view 126. In some sidestream embodiments, ascavenger/scrubber is located just prior to the point of injection of NOinto the inspiratory flow, only scrubbing gases from the NO generationdevice. In some sidestream embodiments, a scavenger/scrubber is locateddownstream from the NO injection site, scrubbing the entire inspiratoryflow.

The system can also be configured to enable the delivery of nitric oxidein either a sidestream or a mainstream mode. In some embodiments, acontroller has two or more cartridge slots that can receive either asidestream or a mainstream cartridge. The controller can generate plasmain the cartridges simultaneously, thereby supporting multiple treatmentsat once in any combination of mainstream and sidestream operations. Insome embodiments, the controller can have a single cartridge slot andthe cartridge can be used in either a sidestream or a mainstream mode.

Switching between sidestream and mainstream modes can be achieved in avariety of ways. In some embodiments, a selector switch/valve canmanually reroute gas between a mainstream path and a sidestream path, orbetween two mainstream paths. In some embodiments, it can be achievedusing software, such that a user can interact with the system, forexample, with one or more buttons or a touchscreen of a user interface,such that the software can control an electromechanical apparatus toreroute flow of gas. In some embodiments, it can be achieved manuallywith a selector switch and software detection of switch position. Oncesoftware detects the change in switch position, it can alter air pumpspeed, air flow rate or plasma generation parameters to provide thedesired nitric oxide concentration to the new destination. In someembodiments, gases can be rerouted passively to the sidestreamapplication when the sidestream tubing is connected to the controller orcartridge. In some embodiments, gas can be switched between thesidestream and mainstream paths automatically based on a measuredparameter from the environment, patient, or another source.

In some embodiments, the controller can have more than one fullyredundant flow circuits, each with a main flow input gas connection, amain flow output gas connection, main flow measurement, and a plasmagenerator with independent gas source. The redundant flow circuits allowthe controller to support more than one mainstream functionsimultaneously. For example, the controller can support a mainstreamventilation circuit and a mainstream respiratory manual ventilationdevice circuit. When support of more than one separate NO application isnot required, the additional circuit(s) can serve as a back-up to thefirst circuit. Engagement of the second circuit can occur based manualinput (a lever position for example) or automatically (for example usinga solenoid valve). It is common to have a filter/scavenger as part ofthe system which could be located between the plasma and ventilator flowgases or in-series with the ventilator gas flow. Referring to FIG. 6, acontroller 150 is illustrated with two independent flow circuits tosupport ventilator and manual ventilation function simultaneously. Eachflow circuit includes an air pump 152, 160, a plasma chamber 154, 162,and a filter/scavenger 156, 164 that couples to a main flow line havinga flow sensor 158, 166.

In some embodiments, the controller receives flow from an external gassource, measures that flow and supplements that flow withplasma-generated NO at a rate consistent with the user-requested nitricoxide concentration. The gas source can be a ventilator, a compressedgas cylinder, a wall gas outlet, gas blender or other type of gas sourcethat is configured to provide reactant gas to the system.

FIG. 7 depicts an embodiment of a system that sources ambient air as thereactant gas for plasma generation that is separate from the main gasstream. The system of FIG. 7 includes a plasma generator 170 thatintakes ambient air or gas. The output of the plasma generator 170 flowsthrough an optional filter/scavenger 172. The system also includes aninput gas connection 174 that takes in the main gas. The output of theinput gas connection 174 flows to a flow measurement device 176. Theoutput of the filter/scavenger 172 or the flow measurement device 176can flow through an output gas connection 178 and out of a main gasoutlet.

FIG. 8 depicts an embodiment of a system with one or more redundantplasma generators and scavenger for safety. The system of FIG. 8includes first and second plasma generators 180, 184 that are coupled tofirst and second optional filter/scavengers 182, 186. It should be notedthat a filter/scavenger can have filters before the scavenger, after thescavenger, both before and after the scavenger, or have multiple filtersdistributed along the scavenger flow path. The system also includes aninput gas connection 188 that takes in the main gas. The output of theinput gas connection 188 flows to a flow measurement device 190. Theoutput of the second filter/scavenger 186 or the flow measurement device190 can flow through an output gas connection 192 and out of a main gasoutlet.

In some embodiments, the sample line connects to a “T”-fitting that isinserted into an inspiratory flow path. In one embodiment, the“T”-fitting is also used to measure gas flow within the inspiratorylimb. Gas flow may be measured using one or more lumens for adifferential pressure method. Flow can be measured based on the entireflow or within a side-stream of the inspiratory flow. In one embodiment,a flow sensor resides within the “T”-fitting. In one embodiment, NOcontaining gas is introduced to the inspiratory flow within the sampleline “T”-fitting (FIG. 9). In one embodiment, a scavenger/scrubberand/or filter are included as a component in the “T”-fitting (FIG. 9).In one embodiment, a “T”-fitting scavenger/scrubber is used in additionto a scavenger/scrubber located within the controller/cartridgesassociated with NO production.

FIG. 10 depicts one embodiment of the injection end of sidestreamdelivery line 200 with two parallel flow paths 204, 206 with a means,such as a flow diverter 202, to select which flow path is active. Eachflow path can contain a scavenger cartridge 208, 210 that is removablyconnected. NO product gases from the NO generation device travel throughone flow path until the scavenger is exhausted, then the product gasflow is redirected to the other flow path and scavenger. A scavengercartridge can be replaced in one path while the other path is scrubbingthe product gas flow. Check valves 212, 214 at the end of each of theparallel paths prevent reverse flow into the unused chamber. A similardual-path design could be made within the “T”-fitting 216, itself, sothat patient inspiratory air flows through one or two scavenger paths.

A similar dual-path design could also be utilized in a mainstreamembodiment so that inspiratory gas delivery is not interrupted when ascavenger cartridge requires replacement. In an embodiment, an NOgeneration system is provided that uses a high voltage (HV) triggercircuit or waveform generator that can continue treatment in the eventof control software crash and/or user interface crash. In an embodiment,an NO generation system is provided that filters, scavenges, andcharcoal-filters incoming gas to remove impurities and increase NOpartial pressure in the exhaust gases. In an embodiment, an NOgeneration system is provided with redundant HV trigger circuits and airpumps, electrode assemblies, batteries, and filter scavengers.

Manual Ventilation

A manual ventilation device (for example, a respiratory bag) can alsoinclude an NO generation feature. The NO-generating portion of themanual ventilation device can be an accessory to a manual ventilationdevice or integrated into a manual respiratory device. In someembodiments, the NO generation portion can include a control circuit, aHV circuit, electrode assembly, scavenger and filter at a minimum forconstant NO production. In some embodiments, air flow and/or bagactivity (pressure, deflection, strain) can be measured in order tomatch NO production with respiratory rate/volume. The control circuitcan activate the HV circuit and related plasma generation based on, butnot limited to, one of more of the following inputs: desired NOconcentration indicated by the user, ambient temperature, ambientpressure, plasma chamber pressure, gas flow rate, and O₂ level in thegas. In some embodiments, the device generates a plasma in the gas thatflows to and fills the respiratory bag. The device may be located inseries before the gas supply for the bag or it may generate NO in aparallel path. In some embodiments, the device includes a pump that ituses to source atmospheric air for the plasma chamber. In someembodiments, the NO generation portion can be located between the manualventilation bag and the patient and generates NO in the gas emitted fromthe bag. In an embodiment, the device can generate plasma for a setduration during each manual inspiration (for example, each squeeze ofthe bag) detected. When the bag of a manual ventilation device is filledwith NO-containing gas, the device can include a scavenger after the bagsince the time for a given NO/NO₂ molecule to leave the bag is notcontrolled. When atmospheric air is sourced for NO generation, the pumpshould prevent retrograde flow through it when off, or a valve should beused (for example, passive one way, or active) to ensure NO flow towardsthe patient and the air path does not present a leak to the system. Insome embodiments, in which NO generation takes place in parallel to thebag with the same gas that fills the bag, a one-way valve can be used toprevent gases flowing backwards through the NO generator during patientexhalation.

FIG. 11 depicts an example of mainstream support of a manual ventilationdevice 224. A controller 220 receives gas from gas source 222, measuresgas flow and supplements gas flow with prescribed level of NO as itpasses to the manual ventilation device 224.

FIG. 12A shows an embodiment of an NO generator 230 in series with amanual bag 232. The air source can be any reactant gas, includingatmospheric air or from a compressed gas source. Check valves before andafter the bag can be used to direct flow towards the patient using amask 236. A scavenger 234 is located after the bag because it is thelast part of the airway before the patient and the residence time of NOin the bag is not controlled unless the bag is completely emptied witheach breath.

FIG. 12B shows an embodiment of a system where NO is generated inatmospheric air and blended with another gas stream before entering thebag 242. A separate component (not shown) may be necessary to titratethe NO flow with other gas stream. Alternatively, the NO flow rate canbe modulated with the speed of the pump 240 and plasma activity in theNO generator 238. Check valves (not shown) can be used to direct flowthrough the bag 242 and a scavenger 244 to the patient using a mask 246and from the patient to atmosphere.

FIG. 13A shows an embodiment of an NO generator 250 that generates NOfrom the same high pressure gas source as the bag 252. The NO generatorcan bleed the product gas (NO-rich gas) into the patient airway at aconstant rate or at a pulsatile rate. In some embodiments, a valve 256opens to flow NO-rich gas into the inspiratory flow when a bagcompression is sensed such that the product gas can flow to the patientusing a mask 258. Bag compression can be sensed by pressure within thebag, bag strain, bag displacement, or exit flow from the bag.

FIG. 13B shows an embodiment of an NO generation system 260 thatgenerates NO from atmospheric air and pumps NO-infused air into theinspiratory track between a manual bag 264 and the patient. In someembodiments, a pump 262 runs continuously. In some embodiments, the pumpruns intermittently in unison with bag compressions. In someembodiments, a valve is located between the scavenger 266 and junctionbetween NO flow and bag flow. The pump runs continuously, flowing airthrough the plasma chamber. The valve is closed during the expiratoryphase so that the pressure in the NO-infused air increases. When bagcompression is detected, the valve opens, releasing the pressurized NOgas into the airway. In some embodiments, an accumulator (not shown) islocated between the NO generator and scavenger to provide additionalvolume of NO-laden gas for each breath.

FIG. 14 shows an embodiment of an NO generating device 270 positionedbetween a manual respiratory bag 272 and the patient. The respiratorybag 272 receives incoming air from either a compressed gas source or theatmosphere. Gases that exit the respiratory bag flow through NOgeneration device, where they are supplemented with NO, and then througha scavenger 274.

The system can generate and deliver product gases in the absence of anexternal inspiratory flow. In some embodiments, a cap can be placed overthe input for a bag connection and product gases flow out the output bagconnection. Product gases are produced at the flow rate andconcentration requested by the user. In some embodiments, the devicedilutes incoming sample gases in a quantifiable way so that gas analysissensors are not damaged by high concentration sample gases andconcentrations are in the measurable range of the sensors.

Acute No Generation System

FIG. 15 depicts a diagram shows an exemplary NO generation system 280.The destination for nitric oxide produced can be any type of ventilationdevice, including but not limited to a ventilator circuit, a nasalcannula, a manual ventilation device, a face mask, an anesthesiacircuit, a CPAP machine, an ECMO machine, an oxygen concentrator, or anyother circuit. In the illustrated embodiment, the NO generation system280 includes an air pump 284 that pumps ambient air into the system 280to be used as the reactant gas. The ambient air is pumped into thesystem, for example into a cartridge 282, and into a plasma generator286 which generates NO using one more electrodes positioned therein. AnNO₂ filter 288 is used to filter NO₂ out of the gas from the plasmagenerator 286. The filtered gas is then pumped out to a ventilationdevice to be delivered to a patient. The cartridge 282 includesadditional features, including a flow sensor 290, an air filter 292, anda water trap 294. The system 280 also includes a controller 298 that hasa suction pump 300 and one or more sensors 302. In the illustratedembodiment, the sensors include NO, NO₂, O₂, and sensor chamberpressure/flow.

The controller typically is a reusable device used for nitric oxidetreatment. Some components of the controller can wear and requirereplacement schedules during the life of the system including the sensorpack, the electrode assembly(s), the pump(s), and the valve(s). On amore regular basis, the scavenger cartridge is replaced after a periodof time, for example, days to weeks. The ventilator cartridge can alsobe replaceable in the event of a sensor failure or contamination.

The controller is designed so that no single fault will halt theproduction of nitric oxide. Instead of requiring user intervention whena single fault occurs, the system can provide continuous NO productionwhile notifying the user of an issue. To accomplish this level ofrobustness, the controller can have one or more of redundant features.For example, the controller can include redundant batteries such that,in the event of a single battery fault, there is a back-up battery. Theuser also has the option of connecting AC power or DC power to the rearpanel of the device. Redundant HV circuits can be used such that asecond HV Circuit serves as a back-up to the ventilator circuit and canprovide nitric oxide to a manual ventilation device circuit. Redundantair pumps can be used such that each high voltage circuit is suppliedair from a dedicated air pump. Redundant electrode assemblies can beused such that each HV circuit drives a dedicated electrode assembly.Thus, if one electrode assembly fails or stops working, the system canautomatically switch to using the other electrode assembly. Redundantsensors and actuators (valves, pumps) are also employed to prevent asingle failure in the generation and delivery of NO.

In some embodiments, the system periodically checks the back-up circuitto ensure that it is functional. FIG. 16A depicts how the systemperiodically checks Channel B. This check could be every 10th plasmapulse or a single check per day, for example. It will be understood thatany measurement of time or plasma pulse can be used to perform a systemcheck on the redundant components. FIG. 16B depicts a failure in ChannelA. The system begins using Channel B for all nitric oxide production toreplace Channel A. In some embodiments, the system can use both channelsequally with the presumption that they will not both fail at the sametime. In cases where both scavenger paths are being used for nitricoxide generation and one channel fails, the second channel is used tomatch the prior NO production or its maximum production limit, whicheveris less. In some embodiments, the system can alternate at regularintervals between electrodes to improve electrode life. In someembodiments, the two channels are used simultaneously. This can have anadvantage of increasing total NO production capacity of a system.Simultaneous use also decreases the temperatures and wear rate of eachchannel, reducing thermal degradation of components and electrodesputtering. Whenever the gas flow is changed from one channel toanother, the previous flow channel is flushed with non-NO-containing gasto remove the NO-containing gases generated.

The system can also have more than one, for example, two independentscavenger paths to address the potential of scavenger path wear and/orobstruction. In cases of maximal nitric oxide generation, the system canutilize both HV circuits and scavenger paths simultaneously to doublethe nitric oxide output.

FIG. 17A depicts an embodiment in which the dual electrode assemblies(plasma chambers) are located within the disposable cartridge, as willbe discussed in more detail below. NO₂ scrubbing features are not shownin the figure but can connect to the electrodes to scrub gases afterthey pass through the plasma generated at the electrodes. The cartridge320 shown in FIG. 17A includes an enclosure 322 that houses a controlboard 330, a sensor bank 346, and dual electrode assemblies 372, 374located within a ventilation cartridge 370 and in communication withhigh voltage circuits 362, 366. The control board 330 includes a buzzer332, a charging circuit 334, a power circuit 336, and a flow/pressurecircuit 338, with connections with batteries 358, 360 and AC and DCpower 324, 326. The control board 330 is in communication with a userinterface 328 and a watchdog circuit 342 having an alarm 340 and abuzzer 344. FIG. 17B depicts an embodiment of a cartridge 380 in whichthe dual electrode assemblies 384, 386 are located within the enclosure382 of the cartridge 380. FIG. 18 depicts a schematic showing all thecomponents of an embodiment of an NO device 390, including control board394, a power management circuit 392, and electrode assemblies 396. Aplasma chamber can be part of the controller or part of the cartridge,as will be discussed in more detail below.

Reactant Gas Intake and Flow Controllers

Various components can be used to take reactant gas into the NOgeneration system. In some embodiments, the reactant gas can passthrough a gas filter, as shown in FIG. X. In some embodiments, the gasfilter has a 0.22 micron pore size. The filter can be used to removeparticulate from the ambient air prior to exposing the air to plasma. Insome embodiments, the reactant gas filter is combined with the NO₂scrubber cartridge to simplify use of the device by reducing use steps.

The pneumatic circuit which supplies the plasma chamber can have aprecisely controlled flow because the reactant gas flow rate through theplasma chamber significantly affects NO generation. The pneumaticcircuit can be constructed in many ways.

Pulsatile Air Flow Mechanisms

A variable flow can be used in some instances to provide NO to apulsatile ventilator air flow, and various mechanisms can be used toachieve a pulsatile air flow. In some embodiments, a motor can be usedthat is concentric with the screw of a ball-screw. The motor can turnthe ball-screw nut, which translates the screw and piston. This can bevery compact and provide adjustable amount of stroke. In someembodiments, a diaphragm can be used and can be “tented” or flat tochange the volume of the chamber to store NO prior to delivery to theventilator circuit. The piston can be driven with a variety ofmechanisms, including a pulley and return spring, rack & pinion, linearmotor, motor with clutch, and pulley.

Various embodiments of techniques for achieving a pulsatile air flow,using pistons, diaphragms, and other mechanisms, are shown in FIGS.19-25. Each of these embodiments can be controlled by an electroniccontrol system using sensor inputs as required from the pneumatic system(chamber pressure, plasma chamber flow rate, reservoir/accumulatorpressure, etc.) and from the patient (inspiratory flow rate, inspiratorypressure, etc.) to achieve the target NO dose delivery. In theembodiment depicted in FIG. 19, a piston 400 can draw in air through aplasma chamber 404 to fill an accumulator/cylinder 402. The piston 400can push NO out through the filter/scavenger 406 to an outlet 408 to besynchronized with a patient's breathe. Stroke and speed can be variedbased on the patient's lung volume and respiratory rate. In theembodiment depicted in FIG. 20, a pump 410 is used to deliver constantflow to a ventilator circuit to dose the bias flow while a piston pump412 is used to provide boluses of air for additional NO generationduring inhalation. In FIG. 21, the device can accumulate NO produced inthe plasma chamber 420 in the accumulator 422 and releases it withpatient inspiration using one or more valves 424, which can be, forexample, a single proportional valve, or an array of valves with binarystates (OPEN/CLOSED). In FIG. 22, one or more valves 430 are locatedbefore the pump 432 to modulate incoming air flow to the plasma chamber434. Modulation can be done in a variety of means, including adjustableclosure as with a proportional valve or pulse-width modulation of adigital valve. In some embodiments, the pump runs at constant speedwhile the valve is adjusted to variably starve the pump, therebymodulating flow rate and NO production. FIG. 23 depicts an alternativeaccumulator design that uses a diaphragm 440. The diaphragm 440 can beeither an elastomeric or a rigid/stiff material. In some embodiments, arolling diaphragm is used. A valve 442 downstream of the diaphragm 440releases pressure from the diaphragm in a controlled manner as needed todose inspiratory events. FIG. 24 depicts an accumulator/reservoir as achamber with elastomeric or non-elastic diaphragm/balloon 452. Adiaphragm driver 450 (solenoid, ball-screw, linear motor, rack andpinion, linear actuator, etc.) is used to displace the diaphragm 452 asneeded to deliver boluses of gas to the patient. In the embodimentdepicted, the plasma chamber 454 is the first element in the system,however, it can be located in other locations so long as its upstream ofthe filter/scavenger. The further downstream the plasma chamber is, thelower the exposure to NO and NO₂ for pneumatic system components. Insome embodiments, NO can be generated as late as possible but before thescavenger so that the high concentration NO/NO₂ mixture exiting theplasma chamber has minimal time to oxidize and generate higher NO₂levels. FIG. 25 depicts a system that utilizes a piston 460 to drawreactant gas into a chamber 462. Electrodes 464 within the chamber 462arc one or more times to generate NO. The piston 460 pushes the NOmixture out to a patient required by the therapy. In some embodiments,the piston pushes boluses of NO to the patient that coincide withpatient inhalation. In some embodiments, the piston pushes out NO at aconstant rate until the reservoir is empty. Then the piston refills thereservoir, NO is generated and NO delivery to the patient resumes. Thepiston can be driven by a many kinds of linear actuators as listedabove.

The compressed gas chamber can include a variable restrictor on theexit. In some embodiments, the compressed gas chamber can be a volumewithin the manifold instead of an independent component of the system.In some embodiments, a pump supplies a pneumatic reservoir. In someembodiments, the pressure within the reservoir is sensed. In someembodiments, pneumatic reservoir pressure may be used as a signal tocontrol pump speed. In some embodiments, flow from the reservoir iscontrolled by a proportional valve or one or more digital valves. Insome embodiments, air pressure upstream and/or downstream of the flowcontrol valve is sensed to improve the control or regulation of airflow. Pressure within the compressed gas chamber can be regulated by aclosed-loop control using chamber pressure as input to control air pumpactivity. The variable restrictor can act like an analog valve insteadof a digital valve (“digital” meaning discrete valve positions can beachieved, such as fully open, fully closed and half-closed). Thevariable restrictor can also include a digital valve that isPWM-controlled to vary air flow through the spark chamber. In someembodiments, one or more air flow sensors may be used to measure airflow downstream from the flow control valve, as part of an air flowcontrol system.

In some embodiments, various flow paths can be included with independentpumps. In some embodiments, one pump can run to dose the bias flow withNO, and another pump can provide pulses of air to increase pressure tomatch the inspiratory activity. In some embodiments, a single flow pathcan provide both bias flow and inspiratory dosing in the event of afailure in another flow path. Lower dosing of the bias flow can beachieved by varying a valve position to slow air flow or generateintermittent air flow.

In some embodiments, a single pump can move air into a dual path flowcircuit. A fixed orifice and pump rate are tuned for bias flow. The pumpcan maintain high pressure behind the fixed orifice. A variable orificecan open during patient inspiration to add additional flow. In someembodiments, the variable orifice diameter can be held constant for agiven patient treatment and an in-line ON/OFF valve controls flowthrough the variable orifice. In some embodiments, a fixed orifice isnot required because the ON/OFF valve can be intermittently opened andclosed to vary flow.

In some embodiments, the pump can run continuously. A flow director canswitch between the fixed orifice path (i.e., bias flow) and variableorifice path (i.e., inspiratory flow and bias flow). In some cases, anair reservoir can be filled by a smaller air pump that can run morecontinuously. The pump is used to maintain a constant pressure in theair reservoir. A pressurized reservoir delivering air through aproportional valve can be more responsive and provide more instantaneousflow than a pump that needs to accelerate to speed. In one embodiment,the air reservoir consists of a void built into the enclosure of the NOgenerator, rather than a separate component. This enables the reservoirto be a closed shape that takes up unused volume within the enclosure,thereby minimizing device size/volume. Combining the reservoir andenclosure also helps minimize the mass of the overall device.

FIGS. 26A and 26B show an N₂ and O₂ containing gas source with flow paththrough a valve to a plasma source. In FIG. 26A, the proportional valve470 does not close further so that there is always some level of flowthrough the plasma chamber 472. FIG. 26B shows a solenoid valve 474 witha permanent hole that always permits some level of flow. FIG. 26C showsa flow source 478 connected to a plasma chamber where the flow sourcecan be varied in flow rate, pressure or a combination of the two. Theflow source could be a rotary pump, piston pump, blower, pressurizedvessel, fan, etc. The flow source of FIG. 26C could be controlled in away that it flows to flush NO₂ from the system in-between inspiratorypulses. This flushing could cease after an amount of time, air volume,or when the next inspiratory pulse is detected.

High Voltage Circuit, Plasma Generator, and Electrodes

In some embodiments, a plasma generation circuit 480 can include awaveform control circuit 482 and a high voltage circuit 484 as shown inFIG. 27. A waveform control circuit 482 generates a continuous,customizable control wave. The control wave contains multiple controlparameters, including the plasma AC current frequency and duty cycle,the discharge pulse frequency and duty cycle, and the group frequencyand duty cycle. In some embodiments, the control wave is generated by adigital signal processor (DSP). An exemplary waveform generated by ahigh voltage controller DSP processor is shown in FIG. 29. The highvoltage transformer converts low voltage currents into voltage highenough to generate a plasma at the electrode gap according to the input.In some embodiments involving an electrode gap of 2.5 mm, high voltagelevels are on the order of 7 kV.

In some embodiments, the system can operate on alternating current (AC)voltage to the electrodes. The presently disclosed embodiments can alsooperate direct current (DC) voltage to the electrodes. In someembodiments, an AC system can be converted to a DC system by addingadditional components to the system. In some embodiments, a halfwaverectifier diode can be included in the system. For example, therectifier diode can be on the low voltage side or the rectifier diodecan be on the high voltage side with a breakdown voltage greater than15-20 kV. In some embodiments, a 15 kV discharge capacitor is added andcan be located after the rectifier to ensure that voltage polarity isnot reversed. Redesign of the transformers can be achieved with a muchlarger turns ratio and current capacity. In an embodiment, a Litz wirecan be used. As a DC system does not benefit from resonance, a highvoltage level is required. Thus, a high turns ratio in the transformercan be required. A voltage tap can be placed at an appropriate locationin the middle of the transformer turns for the AC application. Whencurrent is drawn from the voltage tap (AC resonant operation), theunused portion of the secondary windings of the transformer are shortedto prevent excessively high voltages from occurring.

The high voltage circuit can be formed from a variety of components, butin some embodiments the high voltage circuit includes a controller toreceive commands, a resonant circuit and high voltage transformer. TheHV circuit receives commands from the controller and interprets thecommands as plasma parameters and creates pulses of current that are fedto a resonant circuit and generates AC voltage. The AC voltage has afrequency that is tuned to the natural resonance of the high voltagetransformer to maximize electrical efficiency. The AC high voltage isapplied to the electrodes to make a discharge and is continuous untilthe pulse ends.

FIG. 28 illustrates an embodiment of a HV trigger circuit 490. The HVtrigger circuit 490 receives DC power 492 and at least one input command494. A processor 496 supplies a switching circuit 498 with a PWM signal(variable duration) to excite a tuned resonator circuit 500. Theresonator circuit 500 excites a HV transformer 502 at a fixed resonantfrequency to generate voltage at a HV output 504, for example, theelectrodes. Measurement of current 506 to the resonator providesfeedback of the plasma function to the processor 496. Additionalfeedback can be provided from an input current sensor 508.

The HV trigger circuit 490 shown in FIG. 28 can have a number ofadvantages, including that the resonant tuning improves nitric oxideproduction efficiency, and it eliminates the need for a dischargecapacitor which improves reliability and prolongs component life. ACoperation of the HV trigger circuit can prolong the life of theelectrodes and can reduce the potential of sputtering metal particlesinto the airstream. In some embodiments, a filter is used to capturemetallic particles within a gas stream. In some embodiments, the filtersize is 0.22 micron. In some embodiments, gas is bubbled through aliquid to capture particles after the plasma chamber. The liquid couldbe water, nitric acid, acetic acid, folic acid, for example.

DSP control of the discharge duration can more precisely regulate thenitric oxide concentration, and DSP control also allows for theautomatic “tuning” of resonance to account for manufacturing variation,transformer characteristics, temperature, and electrode status (gap,wear, temperature). In some embodiments, the system identifies theresonant frequency periodically throughout a treatment to account forchanging conditions. In one embodiment, the system determines theresonant frequency only during power-up. In some embodiments, the systemstores the resonant frequency and updates this stored value periodically(e.g. bi-monthly) in order to reduce the start-up time. In someembodiments, the system will operate slightly off resonance in order tolower the plasma power to produce low doses of NO. Input and/or outputcurrent feedback can automatically sense if the electrode fails tospark, which can allow for autonomous mitigation algorithms. The DSP cancontrol the shape of the AC waveform by controlling its frequency andduty cycle.

In some embodiments, the transformer of the HV trigger circuit is aresonant design where voltage within the secondary side of thetransformer increases until a sufficient voltage is present at theelectrodes to break down the air gap. The voltage required to break downthe air gap can vary with humidity, pressure, gap distance, electrodeshape, electrode condition, and other factors. Having a resonant designwithout a set high voltage level improves reliability of plasmageneration in the presence of electrode and environmental variability.In some embodiments, voltages for breakdown are typically in the 8 kV to20 kV range, however it is desirable to keep voltages to less than 14 kVso that safety standards related to X-ray generation can be applied.

The frequency of the alternating current between the electrodes is theresult of the hardware design and, in an embodiment, typically is therange of 50 kHz to 200 kHz. In an exemplary embodiment, the AC currentfrequency is 135 kHz. In another exemplary embodiment, the AC currentfrequency is 100 kHz. Pulses can be a fixed frequency for a treatment atroughly 100 to 200 Hz. This rate may vary, depending on the application.For example, a neonatal application would require slower frequencies dueto the low amount of NO required. The duration of pulses can also bevaried based on the amount of NO desired. For example, for a typicaladult, the duration is roughly 250 micro-seconds (a 0.25% duty cycle).

The leakage inductance of the primary determines the resonant frequency.The mutual inductance between the primary and secondary determines theresonance of the transformer. The high voltage circuit may be controlledby a 555 Timer, a Complex Programmable Logic Device (CPLD), FieldProgrammable Gate Array (FPGA), microprocessor, or any analog circuitry.Communication to the high voltage circuit from the control software andcontrol circuit can be done using a wired connection such as a serialbus, I2C bus, or a wireless means such as optical, Bluetooth, WiFi orother means.

The high voltage trigger circuit can continue generating plasmaaccording to instructions until it receives an instruction to eitheralter or stop plasma production. The system can continue generatingnitric oxide in the event of control software failure, user interfacefailure, and/or control circuit failure.

The system can include a wireless communication module for communicatingwith various additional components, including but not limited to ahospital patient data system, and other controllers. For example, onesystem could communicate the status of a patient treatment case to asecond system when a cartridge is being transferred between controllersfor transport.

In some embodiments, the ventilator cartridge is transferred from onecontroller to another during transport. Treatment information includingbut not limited to serial number, lot number, system configurationinformation, treatment data history, alarm log, patient log, gasanalysis data history, treatment settings log, expiration date, flowsensor calibration information and other information can be transferredfrom one controller to another controller via a memory device within thevent cartridge. The memory device could be communicated via wiredconnection or wireless means (RFID, Blue-tooth, etc.). Data can berefreshed within the ventilator cartridge at a periodic rate throughoutthe treatment. In this way, the receiving the system reads the ventcartridge and can pick up patient treatment where the prior systemstopped. This sort of transfer could take place during patient transferfrom hospital to ambulance, helicopter to hospital, or in the event thata system fails.

In some embodiments, the water trap has a memory device used to storeinformation including but not limited to serial number, lot number,system configuration information, treatment data history, alarm log,patient log, gas analysis data history, treatment settings log,expiration date, flow sensor calibration information and otherinformation. Billing can be in units of minutes of NO treatment, molesof NO treatment, number of treatments, etc.

An enclosure cooling fan can also be included, with or without anencoder to confirm fan operation. The fan operation can also be detectedoptically or with a flow sensor in line with the fan flow. The fan mayalso have its own closed-loop control based on a temperature input formodulating fan speed. Fan speed may also be modulated based on enclosuretemperature, plasma generation levels, enclosure exhaust temperature,ambient temperature, heat exchanger temperature, and/or other inputs.The fan may source the cooling air from the cartridge or from anotherfiltered inlet in the enclosure. In some embodiments, two fans draw airin through a disposable filter cartridge. In some embodiments, one ormore fans source air from within the device enclosure and blow it out.In some embodiments, exhaust gases are blown down out the bottom of thedevice, addressing fluid ingress concerns.

Various inputs can be used to control the plasma generation levels. Inan embodiment, ambient pressure can serve as an input to the controlalgorithm in determining plasma generation levels for a given nitricoxide output concentration using an ambient pressure sensor. A plasmachamber pressure can be measured within the plasma chamber to determinethe amount of N₂ and O₂ present. An enclosure temperature sensor can beused to detect over-heating in the enclosure. In the event ofoverheating, the system can respond by increasing enclosure fan speeds,increasing nitric oxide gas flow rates, alerting the user, and/oranother other type of notification. An ambient temperature sensor can belocated in a location that is isolated from heat generated by the nitricoxide system, and the measurement from the sensor can be used as aninput to the plasma generation algorithm since colder air is more dense,resulting in improved NO generation efficiency. A humidity sensor can beused to measure ambient air conditions to provide an input into nitricoxide generation control algorithms and estimates. The humidity sensorcan also be used to monitor the humidity in the gas analysis sensorchamber to ensure that sensors are maintained in acceptable humidityconditions, or as an input to controlling sample in temperatures toprevent condensation within the sample line. Gas analysis sensors caneither be mounted individually into the controller, or they can beassembled into a sensor pack such that one operation covers all sensors.The gas line handling the sample gases may be made from Nafion, orequivalent, tubing to prevent condensation of moisture and protectsensors from gas that is too dry, depending on the humidity of the gassample. Gas samples for the analysis sensors can be sourced directlyfrom the plasma chamber, from the exit of the scavenger, from thescavenger cartridge, from the ventilator cartridge, or from a locationwithin the patient inspiratory limb. In an embodiment, gas is sampledfrom the patient inspiratory limb, just before the patient Y fitting sothat gas is analyzed just before it enters the patient without addingadditional dead space to the circuit, as would be the case if samplingwas made between the Y and patient. In another embodiment, gas issampled at the exit of the vent cartridge. This presents the advantageof sampling gas that is diluted to patient concentrations while stillbeing in the dry portion of the ventilation circuit, thus notcontaminated by humidity, nebulized drugs and other potentialcontaminants. This option could offer the benefit of not requiring awater trap and filter because it is in the dry portion of the ventilatorcircuit as well as reducing use steps for setting up the system sincethere would be no external sample line. It will be understood by aperson skilled in the art that any number and any combination of thesensors described herein can be used with the system.

In some embodiments, the system can use an NO sensor to detect nitricoxide levels in the gas immediately prior to patient inspiration.Locating the NO sensor near the patient is desirable so that there isminimal effect of additional NO to NO₂ conversion prior to entry intothe patient. One or more NO sensors may be used for redundancy and/orclosed-loop control of plasma generation based on NO output. In anembodiment, a single NO sensor is used for detecting NO levels out ofrange and for limited closed loop feedback. For example, the measured NOsensor levels can increase or decrease the plasma activity by a limitedamount, such as 10%, to adjust the device output.

In some embodiments, the system can use one or more NO₂ sensors toanalyze inspiratory gases prior to entry in a patient. The NO₂ alarmthreshold can vary, but in an embodiment is typically between 1 ppm and3 ppm of NO₂, depending on the application and duration of treatment. Insome embodiments, the system can continue operation in the event of anNO₂ alarm because a sudden respiratory event is more likely than lungdamage at the NO₂ alarm threshold levels.

O₂ levels can also be measured by the system. A system that sourcesambient air to flow through the plasma chamber can dilute gases withinthe inspiratory limb of a ventilator. This can be of particular interestwhen a patient has been prescribed 100% oxygen. Thus, it is desirable toinform the user of the actual O₂ levels that the patient is breathingpost-nitric oxide introduction. For example, the discrepancy in O₂levels between prescribed and actual can be as high as 8% in the 100% O₂case. O₂ measurements may also be used as an input to a controlalgorithm in a system that generates plasma directly within the inspiredgases. As O₂ and N₂ levels approach a Stoichiometric ratio of 50/50, NOproduction levels improve. Thus, a decreasing amount of electrical powercan be required to generate a given amount of NO. Without considering O₂levels in the plasma generation algorithm, the patient is at risk ofreceiving more or less NO than prescribed. In an embodiment, a membrane,such as one used in an oxygen concentrator, can be used to increaseoxygen levels in air prior to entry into the plasma chamber, therebyincreasing NO production efficiency.

In some embodiments, a sample gas pump can be located in the system topull sample gases from the inspiratory flow limb in the ventilatorcircuit to the gas analysis sensors and on to the atmosphere. Commonlyused gas analysis sensors rely on an electrochemical process. Thesensors have slow measurement frequencies, typically at 30 to 60 secondintervals. Commercially available NO delivery systems pull the gassample at a constant flow rate. This averages the NO concentration withrespect to time. With ventilator flow, however, flow rates andconcentrations can vary in time. For example, if the patient received100 ppm NO during inspiration and inspiration represented 10% of therespiratory period and exhalation took place the remaining 90% of therespiratory cycle, the patient would be receiving on average 100 ppm NO.Gas analysis sensors, however would average the concentration of gassensed over the entire respiratory cycle and report a concentration of10 ppm. Thus, a constant flow rate of the sample pump can generateinaccurate gas concentration readings.

One way to improve the accuracy of gas analysis readings is to vary thesample line pump rate as a function of patient inspiratory rate. Areasonable estimate for this is ventilator circuit inspiratory flowrate, however additional considerations for ventilator bias flow may benecessary. In the example above, the sample pump would only pull samplewhen the patient was inspiring, thus the gases analyzed would be at thesame concentration as what the patient inspired, i.e. 100 ppm NO. Oneway of varying the sample pump flow would be to turn the pump off (zeroflow) during patient exhalation and only turn it on during patientinhalation.

Ventilator treatment with bias flow can affect the measured accuracy ofinhaled NO as well. If the sample pump is stopped during exhalation(when bias flow is shunting to the expiratory limb and not entering thepatient), the concentration of bias flow is not measured, therebyimproving the accuracy of the measurement of inspired NO concentration.

In the event that gas analysis sensors require a constant flow of gas,the system could pull sample gas from a source other than the ventilatorcircuit during patient exhalation. An example of another source would beambient air. The controller could calculate what the measurement shouldbe based on the known sample time from the inspiratory limb vs.alternative source and concentrations sensed.

In some embodiments, an approach to providing the gas analysis sensorswith a gas that is more representative of the gas the patient isinspiring is to have a side-stream accumulator/mixing chamber parallelto the inspiratory limb of the ventilator. Typically, the volume of themixing chamber is at least equal to the volume of gas pulled by thesample pump in one respiratory cycle so that the sampled gas representsan average of what the patient inspires. In the example above, thedevice would measure 10% NO. Coupled with the vent flow information,however, the controller would also know that the patient is onlyinspiring 10% of the time. Thus, the device could apply a factor to themeasured data as follows: NO concentration to indicate=measured NOvalue/% inspiration time, where the measured NO value is the valueindicated from electrochemical cells that have averaged the NO levelover the entire respiratory cycle and % inspiration is the fraction ofrespiratory cycle time in units of % that the patient is inspiring.

A sample gas flow sensor can also be provided. A flow of sample gasesover the gas analysis sensors can be required for representativemeasurements of the ventilator circuit gases. It is possible for thesample line to become obstructed or kinked. The system has a sensor todetect a sample line obstruction and proper function of the gas samplepump. The sensor can be a pressure sensor that measures pressure/vacuumlevel in the sensor chamber or an actual flow sensor in series with thepump, or the sensor can be a flow sensor within the sample line. In thecase of a blocked sample line, the sample line can be purged by runningthe pump in reverse.

The electrode assembly, or plasma assembly or chamber, can be part ofthe controller or part of the disposable components such as thecartridge.

In general, the temperatures involved in generating a plasma are at ornear the melting point of most metals. In automotive applications and NOdelivery system descriptions to date, the voltage applied to theelectrodes has been DC, i.e., there is a cathode and an anode. Electronstravel from the anode to the cathode, eroding the anode over time. Itfollows that in automotive and other applications, high-meltingtemperature materials are only used on the anode.

In some embodiments, AC current is applied to the electrodes. This evenselectrode wear by enabling both electrodes to be the cathode for afraction of the time. With both electrodes serving as cathode, bothelectrodes can be comprised of a high-melting temperature material, suchas but not limited to iridium, platinum, sintered iridium oxide or aniridium-platinum alloy. The electrode does not have to be monolithicconstruction of single material but can be alloys or combinations ofsuitable materials. In some embodiments, an iridium or other noble metalor alloy pad is welded to the end of a metallic, cylindrical substrate.It will be understood that a variety of shapes other than cylinders canalso be used to from the electrodes. The substrate material can be of aless-expensive material, such as copper, nickel, carbon steel or iron.This composite approach not only decreases cost, but it also enablesadditional mounting methods for the electrodes. For example, carbonsteel or iron can be used as these materials are non-toxic, thus anyarcing that contacts the substrate will remain safe.

In some embodiments, the mass of the iridium electrode pad 0.15 g, whichis 360 times greater than a typical automotive iridium pad 0.5 mg. Thisadded mass decreases the temperature rise during plasma generation owingto the larger thermal mass and larger contact patch to the electrodesubstrate materials. By having a large iridium electrode pad, theelectrodes can operate for extended time periods, for example, of onemonth, two months, three months, four months or longer on a pair ofelectrodes.

Various electrode shapes and sizes can be used in the plasma chamber. Insome embodiments, needle electrodes can be used. Needle electrodes cansometimes wear rapidly, increasing the electrode gap and altering NOproduction levels. In some embodiments, a flat electrode surface can beused, as an electrode geometry approaching that of a sphere which willerode more slowly since arcs will initiate from more than one location.

A plurality of pairs of electrodes can also be used in the system. Thecontroller (or plasma chamber, or any other location in which theelectrodes can be mounted) can also include one or more electrode pairsto increase run time between services. In some embodiments, theseelectrodes can be mounted to a manifold so that they are replaced as oneunit. In a system that has multiple electrode assemblies, the system cancycle through the electrodes to minimize over-heating. Alternatively,the system can use the electrodes sequentially. Each electrode couldhave a dedicated high voltage transformer or a switching unit like adistributor could be used to energize each electrode from one HVtransformer. FIG. 30 depicts an exemplary embodiment of how an electrodemanifold 520 doubles as a heat sink and can have cooling fins on it.

As electrodes can wear, it is possible to position electrodes in thesystem to increase the ease of replacement. In some embodiments,electrodes can be packaged individually with their own plasma chamberfor easy replacement. The assembly can includes other optional features,such as a heat sink. Electrode activity can also generate coatings ofsputtered materials on the plasma chamber walls. By making the plasmachamber replaceable with the electrode assembly, decreases inperformance due to electrical shorting across sputtered materials can beprevented. In some embodiments, the plasma chamber includes EMIshielding material to minimize radiated emissions from the plasmaactivity. The EMI shielding material is typically electrically coupledto shielding over the high voltage conductors to the electrodes which,in turn, is electrically coupled to electrical shielding covering thehigh voltage transformer. In some embodiments, EMI shielding isconnected to DC Power supply ground. In some embodiments, the electrodeassembly includes pneumatic connections (tubes, fittings and the like)to facilitate connection to the other components of the gas pathway. Gasflow to the electrode could be through the spark chamber withindependent entry and exit points as shown in FIG. 31A, FIG. 31B, andFIG. 31C. FIG. 31A, FIG. 31B, and FIG. 31C depict various views of anembodiment of a dual electrode assembly 530 with cross-flow with apotting material 532, a heat sink 534, and a plurality ofautomotive-style spark plugs. Heat exchanger and gas path can be madefrom extruded metal. FIG. 32A and FIG. 32B depict various views of anembodiment of a single electrode assembly 540 in which the entry andexit point for gas flow could be the same opening so that gases enter ablind hole in the electrode assembly 540 and travel back out the sameentry point. In some embodiments, the broadband EMI generated from thegeneration of plasma can be mitigated by shielding the electrodeassembly by shrouding the electrode in a Faraday Cage.

In embodiments where non-electrically conductive gas passages connect tothe plasma chamber (plastic tubes for example), EMI will travel alongthe length of the gas passage until the passage bends, at which pointthe EMI exits the side of the passage. Shielding can be placed aroundthe passageway to absorb EMI as it exits the passageway. In someembodiments, an electrically conductive spring connected to ground isplaced around the outside of the gas passageway to absorb EMI emittedfrom the plasma chamber. In some embodiments, a tubular woven structureof electrical shielding is placed around the gas passageway andconnected to ground. In some embodiments, electrically conductive tapeis wrapped around the gas passageway. In some embodiments, thepassageway, itself, is made from a conductive material (stainless steelfor example). The minimum length of the shielded portion of thepassageway can be from the plasma chamber to the first bend inpassageway that has sufficient angle to completely absorb the EMI. Itfollows that the magnitude of bend sufficient to absorb all the EMIwithin the passageway is a function of the diameter of the passageway(for round openings). Changing the aspect ratio of the passagewaycross-section (ovalizing for example) could maintain similarcross-section, while decreasing the amount of bend necessary to absorbEMI with electrically conductive shielding.

FIG. 33 depicts an example of an electrode assembly 552 mounted to acontroller 550. In the illustrated embodiment, pumped air andNO-containing air are coupled to the electrode assembly 552 with adual-lumen connector. The assembly includes an O-ring or lip seal 554.The plasma from the assembly 552 is pumped into a filter 556 and ascavenger 558.

Various electrode designs can be used for NO generation. In someembodiments, automotive-style plugs can be used for NO generation,however they can include resistors and more mass and strength thanrequired. An automotive spark plug is designed for strength with aceramic insulator and heavy metal ground electrode. In the interest ofcost and mass, a custom high voltage electrode is desirable. FIG. 34shows a high voltage electrode that can be manufactured and installedeasily. FIG. 34 illustrates an embodiment of an electrode assembly 560with a blind hole 562 (dashed lines at bottom). Composite electrodes564, 566 can be inserted into the ends (right and left). In someembodiments, the electrode assembly 560 of FIG. 34 can be manufacturedcreating composite electrodes by fusing iridium (or other noble metal oralloy) pads to a metallic shaft (for example, copper). O-rings 568, 570can be inserted into each end of a sleeve. The sleeve 572 can beconstructed from PEEK, glass, ceramic or another inert, non-conductivematerial. Electrodes are inserted through the O-rings from either endinto a sleeve. A gap tool is inserted into the hole for air connection.End plates 574, 576 are slid onto each shaft. Electrodes are lightlypressed from either side against the gapping tool. End plates aresoldered to the shafts, locking in the gap. The electrodes can be heldin place using a variety of techniques, including but not limited to aninterference fit, adhesive, threaded fastener, and other means. In someembodiments, the end plate can mechanically snap on to the end of theglass sleeve as shown in FIG. 35, which illustrates an embodiment of anelectrode assembly 580 with end plates 588 that clip to the sleeve 586and solder to the electrodes 582, 584.

Having a single hole for air connection enables the user to insert anelectrode assembly from one side with a single action. Various types ofretention features can be used, including but not limited to detents,snaps, clamps and other means, to keep an electrode assembly in positionwithin a controller.

A custom electrode assembly can interface with a controller byregistering the electrodes with electrical contacts in the controller. Adual-lumen nipple from the controller can be inserted into the hole inthe side of the electrode assembly to deliver air and remove NO-ladenair.

FIG. 36 illustrates an embodiment of an electrode assembly 590comprising a sleeve 596, a composite electrode 592 (copper shaft withiridium pad), O-ring seals 598, 600, and end plates 602, 604. Theelectrode assembly 590 can be inserted into a controller with highvoltage electrical contacts contacting each end of the electrodeassembly 590 and a dual-lumen nipple 606 inserted into the airconnection hole. The composite electrode may have a step in thediameter, flange or other feature that makes the electrode bottom outinto a hole at a specific depth. FIG. 37 illustrates embodiments ofelectrodes with features for bottoming out. During manufacture of anelectrode assembly, individual electrodes are fabricated. In theembodiments shown, a high-melting point metal tip is connected to lesscostly substrate material. This composite approach can reduce cost andimprove heat transfer away from the plasma in many cases. To assemble anelectrode assembly, in one embodiment, each electrode is pressed into aframe. By providing a shelf or positive stop on the outer profile ofeach electrode, the electrodes can be pressed into until they bottomout. In other embodiments, the electrodes are pressed into a plasmachamber, manifold or other pneumatic component of the system. In otherembodiments, the electrodes are pressed into a frame until a targetelectrode gap has been achieved. In one embodiment, electrodes arelocated and held in place within the plasma chamber housing with apress-fit. In one embodiment, the plasma chamber is over-molded onto theelectrodes. In one embodiment, electrodes are held in place with a setscrew.

In some embodiments, flow of air through the electrode assembly goesacross the electrode gap. FIG. 38 illustrates an embodiment of anelectrode assembly 610 showing air inlets (bottom left and upper right).Air flows into the electrode assembly on one side and out the opposingside. FIG. 39 illustrates an embodiment of a cross-flow electrodeassembly 620 showing end-plate geometry. The hole in the corner of theend plate can be used for soldering a wire to it or fastening the endplate to the sleeve with a threaded fastener. The corners of the endplate can be rounded to reduce the potential of electrical dischargefrom the end plate.

Air flow within the electrode assembly can be from one side to theother, as shown in FIG. 39. In some embodiments, the flow can be fromone side to an adjacent side. In some embodiments, air enters from oneside, travels axially in parallel with the electrodes and then exitsfrom the same side. This design shares the benefit of being insertedwith a single action. For example, a person installing an electrodesimply pushes the electrode assembly onto mating pneumatic connections,simultaneously establishing electrical connections.

There are various ways to accomplish plasma control. In someembodiments, a plasma energy level is controlled by varying the inputvoltage to the primary coil in the high voltage circuit. A huntingalgorithm or a sweeping algorithm can be used that detects the resonantfrequency of the HV circuit when the system is first turned on. Thisaccommodates for manufacturing variance in the transformer and electrodevariance (for example, gap, wear, corrosion).

FIG. 40 illustrates an exemplary graph of an approach for determiningthe resonant frequency for the high voltage circuit. A sweepingalgorithm can be used for alternating current frequency (not sparkfrequency) to find a resonant frequency to accommodate for electrodewear, and can sweep high to low or low to high. It can be possible todetune the resonance when lower NO production is desired. This reducesthe amount of energy in the plasma, resulting in reduced NO production.

In some embodiments, a pressure sensor can be used to detect plasmageneration. Pressure increases because the plasma heats the air andmakes the air expand. In some embodiments, a microphone can be used todetect plasma occurrence. In some embodiments, noise in the current inthe primary winding of the HV circuit can be used to detect plasma. FIG.41 illustrates an exemplary graph showing the use of noise to detectplasma.

The initiation of plasma can require additional energy, increase RFInoise, and increase electrode erosion. Thus, in some embodiments, plasmacan be generated continuously and only vary N₂ and O₂-containing gasflow rate and/or plasma intensity. In addition, continuous plasmageneration can create more NO than is needed to treat the patient. Toprevent this, the system can have more than one electrode assembly, witheach electrode assembly having a different electrode gap. Smaller gapscan be used to generate lower levels of NO, as needed for neonateapplications. Larger gaps (2-3 mm for example) can be used to generatehigher doses of NO.

The electrode assembly, as noted above, can have a variety ofconfigurations. In some embodiments, a plurality of short-gap sparkplugs can be used to reduce electro-magnetic interference (EMI) andreduce high voltage requirements. A two-electrode design can be usedwith a third body that provides a shield for the plasma. A returncurrent from the spark plug can be used as an indication of the statusof the electrode, such as loss of the iridium pad or sensing that theperformance is waning. Use of color/optical properties of the spark canalso be used as an indication of electrode condition.

It is possible that the position of the ground electrode in anautomotive-style electrode assembly with respect to air flow can have a10-12% effect on NO generation. By locating the ground electrodeupstream of the electrode gap, there are two significant benefits: A)shielding of the plasma arc, which is susceptible to “bending” in thepresence of substantial flow. By using the ground electrode as a flowobstruction, the plasma arc may be produced in a less turbulent region,which may aid in the stable production of NO. B) any particles,specifically iridium oxide, which may be sputtered from the electrodesurfaces, may deposit on the ceramic center electrode insulatordownstream without creating a shortened creepage/clearance path to theground electrode. Thus, the electrode assembly can require indexing(i.e. a specific orientation with respect to gas flow) to ensureconsistent performance. In some embodiments, a drop-in electrodeassembly can be used with an indexing feature. This can work because NOgeneration does not involve high pressure and temperature, so threadsare not required. For example, an indexing feature can include a hexagonshape with a ground-off corner, a peg emanating from the plug (groundelectrode, ground electrode shell, insulator, center electrode), agroove in the ground electrode shell, a unique spline design in theground electrode shell, and/or a unique over-molded shape over theconventional electrode assembly. A visual indicator can be used toassist a user in orienting the electrode assembly correctly. Forexample, a colored dot on the electrode assembly can aligns with acolored dot on the manifold.

The use of off-the-shelf spark plugs, such as automotive or yard-toolspark plugs, can present a risk to the patient by not generating theappropriate amount of NO and/or introducing toxic materials into the airstream. In some embodiments, a unique electrode assembly interface canbe used with the manifold. For example, a thread-less ground electrodeshell with one or more of the hexagonal nut corners removed can be used,as shown in FIG. 37. The outer diameter of the thread-less section canbe less than the diameter of a threaded spark plug, thereby preventinginsertion. The electrode assembly can be retained by a retaining platethat fastens to the manifold and applies a clamping force to theelectrode assembly. The electrode assembly shell can have a sealingsurface that compresses an O-ring against the manifold.

The electrode assembly can be sealed to the manifold with a variety ofmechanisms. In some embodiments, as shown in FIG. 42, an O-ring can beused (Viton, or fluorinated materials are preferred) with an electrodeassembly 630. In some embodiments, the O-ring seal is an axialcompression as shown in FIG. 42, where the clamping force maintains theseal. Compression can be applied by retaining plate that fastens to themanifold. Compression of the O-ring can be controlled by compressionlimiting features in the plate, plug, or manifold. In some embodiments,a retaining plate can be used and can be electrically conductive in thecase of a plastic manifold (Teflon for example). In the case of anelectrically conductive manifold, the retaining plate could benon-conductive, such as plastic. In some embodiments, the O-ring sealsradially against a bore in the plasma chamber.

Electrode materials can sputter from the electrodes and enter theventilator airstream, which can be harmful to the patient if theelectrode materials are toxic. In some embodiments, electrode assemblyground electrode shell can be made from steel and or iron, which arenon-toxic. Iron and steel are also magnetic, thus a magnet could beplaced in the system down-stream from the electrode assembly to collectsputtered magnetic electrode particles.

FIG. 43 depicts an example of an electrode assembly 640 designed forimproved NO gas purity. The noble metal electrode pads are attached onthe back surface only so that only the electrode is presented to theplasma. The noble metal could be platinum, iridium, another high-meltingpoint metal or alloy thereof. The metal pads are connected on their backside to an electrically conductive substrate. The substrate holds theelectrode pad in the correct location and conducts electricity to thepad. The substrate shown in FIG. 43 is made from sheet metal, whichfacilitates electrical connection to the assembly via a tab connector.Bosses around the tab connector provide a means for sealing aninsulative boot around the connector to prevent electrical creepage.Ridges between the electrodes on the bottom surface increase the surfacedistance between the electrodes to further minimize electrical creepagepotential. The body of the assembly (shown in orange) is made from anon-electrically conductive material such as plastic or ceramic. One ormore holes in the body enable the body to be secured to the rest of thesystem via screws. In one embodiment, the body itself is threaded forengagement into the system.

FIG. 44A presents a drawing of an electrode pad 650 with attachment 654,such as a weld, to an electrode substrate 652. One problem that canoccur in plasma generation is that the plasma arc can be emitted frommaterials adjacent to the electrode pad, depending on their proximity tothe arc, thermionic work function, and geometry. During NO generationvia plasma, it is desirable to control the plasma so that it is onlyemitted from the electrode pads. The design in FIG. 44A depicts anelectrode pad 650 with a larger area towards the plasma (right in theimage) and a smaller end towards the substrate. The smaller end isattached to the substrate via welding, soldering, crimping, press fit orsome other means. The electrode pad can be created by turning on alathe, wire EDM, casting or another process.

The substrate material for the electrode assemblies shown in FIG. 43 andFIG. 44A are typically metallic. Unlike typical spark plugs that have anickel coating, medical applications require a more inert material. Insome embodiments, stainless steel is used, owing to its biocompatibilityand weldability to noble metals. In some embodiments, titanium or atitanium alloy is used, offering benefits in thermal conductivity,biocompatibility, weldability (high melting temperature), and absence ofnickel and chromium (toxic materials).

FIG. 44A depicts an electrode assembly with a cylinder around theelectrode pads. The cylinder provides a surface to capture sputteredmaterials from the electrodes that can be replaced with the electrodes.Without a surface to capture sputtered materials, the walls of theplasma chamber could build up sufficient sputtered materials to beelectrically conductive, thereby presenting a short circuit for theelectricity and decreasing NO generation. Other shapes could also serveas a collector for sputtered materials, including a flat surface 670between electrode pads 672 and the assembly body 674 as shown in FIG.45, however a closed shape like a tube or square-extrusion is thegreatest potential to decrease short circuits between the electrodes.Also shown in FIG. 45 are extensions from the electrodes that serve ascooling features. These cooling features help prevent over-heating ofthe electrode which can lead to increased wear and damage to insulatormaterials.

FIG. 44B depicts the electrode assembly of FIG. 44A with insulation 656around the entire length of the electrode except for the tip. In someembodiments, the tip is made from a noble metal, such as iridium orplatinum. Insulation 656 around the electrode prevents the plasma arcfrom contacting the sides of the electrode when energized, therebycontrolling the types of materials that may be sputtered off theelectrode. Furthermore, the electrode increases the electrical creepagedistance from one electrode to another electrode, thus decreasing thepotential for a short circuit.

FIG. 44C depicts an electrode assembly 660 for use in an NO generationdevice. The assembly 660 includes two electrodes 662, 664 made fromsheet metal. On one end, the electrodes are shaped like a tab-connectorfor electrical connection. The insulative frame 666 provides electricalinsulation between the electrodes 662, 664 and maintains the electrodegap. Bosses around the electrode tab connectors provide a surface for aboot to seal against when an electrical connection is made. A ridgebetween the two bosses on the top surface provides additional creepagedistance between the two electrodes. On the bottom of the figure, thereis a tubular structure 668 around the electrode gap. This tubularstructure provides a surface to receive sputtered electrode materials.By providing a sacrificial surface for sputtered materials, sputteredmaterials do not build up on the plasma chamber wall, increasing thepotential for an electrical short due to creepage or arcing directly tothe plasma chamber wall. The tubular structure 668 can be made out ofeither an electrically insulative material or an electrically conductivematerial if proper clearances are maintained. The bottom edge of theelectrodes feature additional material that acts like a cooling fin 669in the reactant gas air flow to dissipate heat from the electrodes 662,664 and minimize sputtering.

Plasma generation can generate considerable electromagnetic radiation.The largest source of emissions is the high voltage circuit and theplasma activity. Shielding the electronic circuit, electrodes and plasmachamber help in minimizing emissions. In addition, shortening the lengthof wires in the high voltage circuit can reduce emissions. To that end,it is beneficial to combine the electrodes and high voltage transformerso that there is no length of wire between the two that could act as anantenna. FIG. 46A depicts a combination of electrode assembly and highvoltage transformer. An iron-core transformer 680 is depicted, but othertypes of transformers can be combined with the electrodes 682 to reduceemissions. In one embodiment, a central grounding scheme that connectsall the chassis shielding elements and ties them to DC ground at asingle point absorbs the bulk of the EMI radiation and conducts it toground without being re-radiated.

FIG. 46B depicts an exemplary electrode assembly 690 with a focus onmaximizing creepage and clearance distances. In this embodiment, theground electrode pad 692 is taller than the center electrode pad toensure arcing only occurs to the pad. In some embodiments, the groundelectrode 696 measures 2 mm in diameter and 2 mm tall. The groundelectrode pad 692 is fastened to a ground electrode 696 via welding,soldering or another means. In some embodiments, the ground electrode ismade from stainless steel to minimize the potential for nickel particlesentering the product gas, however carbon steel, titanium and other highmelting point materials have been considered. Both electrode pads aremade from a high melting point material, such as iridium, platinum orsimilar. The center electrode pad can be shorter, such as 1 mm, owing tothe fact that there is ceramic insulation 698 around it that preventsarcing to substrate materials.

The shell of the electrode assembly depicted in FIG. 46B is designed tobe far from the electrode gap. This is to minimize the propensity forside-sparking. In the example shown, the distance from center electrodeto shell is more than 3 times the distance of the electrode gap so thatarcing from center electrode directly to the shell is unlikely even inthe presence of Iridium-oxide deposition on the ceramic insulator 698.An O-ring 700 provides a seal against a mating surface in a plasmachamber or electrode block.

The ground electrode has an asymmetric cross-section with the longdimension tangential to the shell, thereby maximizing distance away fromthe electrode gap. The ground electrode is fastened to the electrodeshell at the outermost location, further maximizing the distance fromthe electrode gap. The bend in the ground electrode is a sharp bend tomaximize distance from the electrode gap. In some embodiments (notshown), an electrically insulative material such as polymer or ceramicis placed between the electrode gap and the ground electrode. In someembodiments, the insulative material is a tube or coating that coversthe length of the ground electrode.

Performance of electrode assemblies with or without embeddedtransformers may vary in production do to electrode gap, transformerwinding variance, conductivity variance and other factors. One solutionto address manufacturing variance is to embed calibration informationwithin the electrode assembly via an RFID or other memory device. Thiscalibration information could consist of a resonant frequency.

Performance of the pneumatic manifold within an NO generation device mayvary as well. In one embodiment, the calibration information for amanifold is embedded within the manifold and is used by system softwareas an input to calculating NO generation parameters. The information canbe embedded into a manifold by RFID, a processor with Bluetooth, barcode, wired memory device and other means. Calibration information canconsist of one or more of the following types of information: a flowrestriction value, pressure sensor calibration information, flow sensorcalibration information, variable orifice transfer function. Themanifold may also have manufacturing and use data embedded and/orwritten to it, such as serial number, lot number, expiration date, firstused date, total amount of run time, total amount of NO exposure, etc.

The purpose of the manifold is to direct the flow of gas through thesystem without leaking. In one embodiment, the manifold is made ofmetal, such as aluminum, stainless or titanium, so that the manifold canact as a heat sink and EMI shield. In another embodiment, the manifoldis made from a polymeric material such as PEEK or Teflon in order toprovide an inert material in contact with the NO, NO₂ and air. Polymericmanifolds may be plated or otherwise encapsulated in conductive materialfor EMI shielding purposes. In one embodiment, the manifold is a splitdesign held together with threaded fasteners with a gasket in betweenthe two halves. The gasket is made from silicone, Tygon, Fluorocarbon(FKM) or other NO-compatible elastomeric material. Gasket compression isprotected from over-tightening by positive stops that control the levelof gasket compression. Compression of the gasket is done with narrowwalls to minimize fastening force on the gasket and provide even gasketcompression. In another embodiment, the manifold is constructed from twoor more components that are ultrasonically welded together. Othermanifold assembly methods may include hot plate welding, laser welding,solvent bonding, RF-welding and UV adhesive, depending on the materialsselected.

In some embodiments, side-sparking can occur. Side-sparking is the termused for arcing between an electrode and a non-electrode surface.Side-sparking occurs when the electrical path of the spark to anon-electrode surface becomes a lower impedance then the path to theelectrode. When this happens there is a change in the discharge currentand the waveform associated with the current discharge. Side-sparkingmay indicate imperfections in the construction of the electrodes.Side-sparking can also occur as the electrode wears at the end of itsuseful life. Side-sparking is undesirable for several reasons: 1)Discharge, other than in the electrode gap is non-deterministic. Thatis, the energy of the discharge is other than expected, and thus the NOand NO₂ production are unpredictable, 2) Discharge to points other thanthe electrodes will sputter other, non-electrode metals into theair-stream. Depending on the materials, the sputtered particles could bepotentially toxic, 3) Uncontrolled discharge may cause the generation ofunsafe current levels in the control circuit which could potentiallydamage the circuit.

By detecting the occurrence of side sparking (or non-sparking),undesirable and/or dangerous conditions may be avoided by switching tothe backup line. In one embodiment, side sparking is detected byanalyzing the frequency content of the input current to the high voltagetransformer. The plasma, when sheltered from direct air flow, as in thecase of electrode indexing mentioned elsewhere in this text, is morestable and lacking in high frequency structure. Contrastingly,side-sparking can have more high frequency content which can bedetected. In another embodiment, a high pass filter is applied to theinput current signal. The high pass-filtered signal is half-waverectified and compared with a known signal. Deviations from the expectedare indications of side sparking. In another embodiment, the averageinput current into the high voltage transformer is compared to anexpected range of values. Current below this range can indicate sidesparking because the plasma has found a lower resistance path.

Current above this range indicates an absence of sparking because theenergy generated by the control circuit is not being delivered to theplasma, and so the controller will increase the current to try to forcebreakdown. In another embodiment, side-sparking is detected by a suddendecline in NO production as indicated by the NO and/or NO₂ gas sensors.In some embodiments, the controller, upon detecting side sparking, willturn off the spark in an attempt to reset it. If resetting the plasmadischarge is unsuccessful, the controller will switch to the backup NOgeneration circuit.

Electrode Design

In some embodiments, the system can include first and second individualelectrodes. In some embodiments, the system can include user-replaceableelectrodes. To facilitate electrode replacement, electrodes can beconfigured in an electrode assembly. This allows for a preset electrodegap that the user does not have to set or adjust. In some embodiments,the electrode assembly includes a plasma chamber with an inlet forreactant gas and an outlet for product gases.

As electrodes wear, electrode material can sputter onto nearby surfaces.For example, with iridium oxide, the sputtered materials areelectrically conductive. This can cause a short circuit that conductselectricity along a surface of the plasma chamber and/or electrodeassembly instead of through an air gap. In some embodiments, anelectrode assembly can include a surface for collecting sputteredelectrode material. This surface is refreshed when the electrodeassembly is replaced. In some embodiments, there is a replaceablesurface within the manifold that can be changed out as needed. In someembodiments, the plasma chamber is replaceable. In some embodiments, theplasma chamber is integrated into the electrode assembly.

In the event that there is shorting along a surface instead of throughthe air gap, the control system can detect this type of electricalcreepage by analyzing the integrity of the analog DC current signalprovided to the switching circuit at the front end of the high voltagegenerator. During abnormal sparking, current finds a lower resistancepath along the sides of the electrode. In some embodiments, the systemmonitors shifts in the level of the current peaks, in order to detectabnormal sparking events.

Depending on the electrode pad material and electrode substrate materialselected, it is possible that the electrode substrate can have a lowerwork function (i.e. propensity to conduct electricity) than theelectrode pad material. In this case, an electrical arc spanning a gapbetween two electrode pads can travel a longer distance to land directlyon electrode substrate material instead of electrode pad material. Insome embodiments, the electrode pad length can be sufficiently long thatthe arc will not reach electrode substrate material. In someembodiments, the electrode pad can be shaped like a mushroom with alarge head facing the electrode gap, thereby presenting only electrodepad material to the arc. In some embodiments, a spacer is placed betweenthe ground electrode and electrode pad where the space has a smallerdiameter than the electrode pad (FIG. 42). The electrode design shown inFIG. 42 shields the welded interface between electrode tip and electrodesubstrate from arcing. The spacer is connected to the electrode pad withlaser welding, soldering or another means to join the materials. Withthis design, an arc is less likely to contact the weld and groundelectrode substrate material, decreasing the potential of introducingmaterials into the airstream other than the electrode tip material.

In some embodiments, noble metals can be used for electrode pad materialbecause they have high melting temperatures and generate higher NO/NO₂ratios. In some embodiments, noble metals can be used and connected toother substrate materials, making a composite electrode. A variety ofsubstrate materials can be chosen, taking various factors into account,including but not limited to safety in the event that an arc comes intocontact, biocompatibility, weldability and cost.

In some embodiments, the substrate material is made of titanium whichoffers advantages in biocompatibility and weldability (high meltingtemperature) over more common substrate materials. In some embodiments,stainless steel is used as a substrate material which offers anadvantage minimal to no nickel content.

Electrode Service Life

Electrodes can fail in a variety of ways including excessive wear thatincreases the gap beyond a usable distance and deposition ofelectrically conductive materials on adjacent surfaces that can providea pathway for shorting. In some embodiments, the NO generation systemhas the ability to detect a failed electrode/electrode set and stop useof an electrode that is not functioning properly.

There are a variety of ways for the system to detect an electrodefailure. For example, failure of an electrode can be detected byanalyzing the current that travels through the high voltage circuit. Theelectrical current through the high voltage circuit is typically verynoisy (multiple frequencies present) during a normal electricaldischarge. Contrastingly, an electrical discharge that travels along asurface (shorting) will have a cleaner signal (less frequency content).This is a detectable event and can be used as criteria for retiring anelectrode from service. The wave shape of the discharge current is anindicator of where the discharge landed. In some embodiments, thecurrent wave shape can be used as a trigger for electrode replacement orscheduling maintenance. In some embodiments, the system stops using aparticular electrode after a predetermined number of missed dischargesor discharges that did not travel across the electrode gap.

High Voltage Circuit

In some embodiments, alternating current (AC) at the electrodes is used.This improves electrical efficiency, reduces weight and evens electrodewear. Furthermore, electrical protection of the user (Means of OperatorProtection, MOOP) is reduced with AC voltage because the peak voltagerequired for electrical discharge with an AC voltage is half themagnitude of an equivalent DC high voltage required. This is because ACvoltage has a positive and a negative peak. In some embodiments, a lowvoltage (˜16 VAC) alternating current is supplied to the primary windingof a transformer and the secondary winding creates an output of roughly7 kVAC. In other embodiments, the input voltage may vary from 6 VAC to100 VAC.

The frequency of the AC voltage is an additional variable that may becontrolled by the system. For optimal electrical efficiency, an NOgeneration device can sweep through many frequencies to determine aresonant frequency of the high voltage circuit. The advantage of thisapproach is that it can account for manufacturing variance in thetransformer, electrodes, wiring, etc. as well as electrode wear. In oneembodiment, the frequency of the AC voltage is determined by selectingthe frequency associated with the maximum (resonant) amount of currentin the circuit before electrical discharge occurs across the electrodes.The actual resonant frequency varies with the electrical design andlevel of wear in the high voltage circuit.

In one embodiment, the resonant frequency occurs in the range of 80 kHzto 150 kHz. In one embodiment, a narrower range of frequencies issearched, 115 kHz to 130 Khz for example, to reduce the amount of timeto conduct the resonant frequency sweep. The search for resonance of thehigh voltage circuit can be done at any time when the NO generationsystem is powered up. In one embodiment, the resonant frequency isdetermined only at power-up. In another embodiment, the resonantfrequency is determined at the beginning of a patient treatment. In oneembodiment, the resonant frequency is determined with each patientinspiration. In one embodiment, the system searches for the firstharmonic frequency. In some embodiments, the system searches for aharmonic frequency. In some embodiments, the resonant frequency ismeasured and stored in memory. The resonant frequency does not changesignificantly from one use to another. Upon the next power-up, thefrequency is read from memory rather than re-established, allowing for aquicker start-up. In some embodiments, the resonant frequency isre-established and updated periodically.

Controller

As explained above, the NO generation system includes a controller thatis configured to control the NO production by the one or more plasmachambers, for example, by controlling the sparking of the one or moreelectrodes in the plasma chambers.

The controller is comprised of an enclosure housing various components.It will be understood by of ordinary skill in the art that variouscombinations of these components can be present in the controller. Also,there may be more than one of some of the components within theenclosure, depending on their criticality to continuous NO production.

The enclosure houses the internal components of the controller andprotects them drop as well as mechanical and fluid ingress. In someembodiments in which the system includes one or more cartridges (as willbe explained in more detail below), the enclosure can also includefeatures to engage the cartridge. In some embodiments, the enclosureincludes at least one cartridge slot that is configured to mechanicallyinterface with the cartridge in a way that ensures the cartridge isremovable and positioned correctly in relation to the controller andprevents the cartridge from being inserted improperly, for exampleupside-down or side-ways. The enclosure and the cartridge slot caninclude features to protect the cartridge and the cartridge slot. Forexample, the cartridge slot can include a passive or active door thatcovers the cartridge slot to prevent mechanical and/or fluid access tothe internal portions of the controller. The door can include a springor other biasing mechanism such that the door can be biased to be in aclosed position. In an embodiment, the door can be configured to closeentirely when a cartridge is fully inserted in the cartridge slot.

FIGS. 47A and 47B depict an embodiment of a controller enclosure 710 andits contents. Air flow through the enclosure is moved via a fan 712 thatsources air from a cartridge 714. The controller enclosure includes aone or more sensors 716, an exhaust 718 and a vent 732, a power switch722, a fuse 724, and a power controller 726. Batteries 736 are alsoincluded as an additional power source. One or more high voltagecircuits 728 and a ground 720 are also included in the controllerenclosure 710. The enclosure 710 also includes a display 715 that isconfigured to communicate and display information to the user regardingNO production and patient information.

The controller accepts AC power from all AC power sources and convertsthe power into a DC voltage using a standard transformer. The controlleras includes a DC power inlet that can accept 12V or 24V to ensureadequate power when operating in a plane, ambulance, or helicopter. TheDC power inlet can also be used to receive power from an externalbattery device for extended patient transport. The external battery canbe connected to the controller enclosure to facilitate transport.

The controller can also include one or more batteries for NO generationin the absence of wall power. Multiple batteries, for example, twobatteries, can be used for redundancy. For example, the duration ofoperation for each battery can be 30 minutes.

The controller includes a control circuit that receives and processesinformation relating to the NO generation system (for example, from acartridge if one is being used) and the patient being treated with theNO. The controller used this information to determine one or morecontrol parameters that can be communicated to the plasma chamber tocontrol NO concentration in the product gas produced in the plasmachambers. In some embodiments, the control circuit receives and/orprocessing information relating to sensor information, and received userinputs. The controller circuit can also send and/or receive informationto and from a user interface, and can control the production of NO bydetermining a plasma chamber gas flow rate, and/or a frequency of thewaveform control circuit AC, and/or a duty cycle of the waveform controlcircuit AC, and/or a discharge pulse frequency, and/or a pulse dutycycle of the plasma activity, and/or a burst count, and/or a burstperiod, and/or a burst duty cycle.

As shown in FIG. 48, an NO generation and delivery device can provide NOduring inspiration using a pulse of constant concentration 737 or apulse with dynamic concentration 738. In one embodiment using thedynamic concentration 738, the concentration of gases in an initialvolume of an NO pulse are higher than the concentration in the balanceof the volume in the NO pulse. By varying the concentration within apulse, the dose delivered can vary within the patient anatomy (lung,airway, etc.). One advantage to this approach is that regions of thelung with greater air exchange that are normally filled first duringinspiration would receive preferentially more NO. In one embodiment, theconcentration within a pulse is varied by altering the plasma parameters(power, frequency, duty cycle, etc.) with a pulsatile flow through theplasma chamber. In another embodiment, plasma parameters remain constantand flow through the plasma chamber is varied to generate variations inconcentration within the product gas stream. In another embodiment, bothplasma parameters and flow parameters are varied to produce variationconcentration within a delivered NO pulse.

In some embodiments, a watchdog circuit can also be included in thecontroller and can be used to monitor the function of the controlsoftware and the high voltage circuits. The watchdog circuit can createalarms in the event of an alarm event or condition. The creation of analarm will not stop treatment to a patient as the pause in treatmentcould potentially harm the patient. Safeguards can be included in theevent of a control circuit failure. For example, in the event of controlsoftware failure, a piezoelectric buzzer with a dedicated battery issounded to bring attention to the user. In some embodiments, a systemcan alert the user if flow through the device is detected and NO has notbeen initiated. This applies to both the ventilator circuit and the bagcircuit.

In some embodiments, a cartridge can include a memory device. The memorydevice can have a variety of uses. For example, the memory device caninclude information that identifies the type of cartridge to decreaseuse errors. Communication to the memory device could be with directelectrical contact to the cartridge or through wireless means, such asRFID. In some embodiments, the information on the memory device andcommunications to and from the memory device are encrypted to ensuredata security and prevent counterfeiting. In some embodiments, an actualmicroprocessor, sensors, and/or memory could be placed on the cartridge.In some embodiments, a microprocessor, sensors, and/or memory areseparate from the cartridge and can communicate with the cartridgewirelessly or through a wired connection.

In some embodiments that utilize a cartridge, the memory can be used tostore information relating to the various cartridge options. Forexample, by knowing what kind of cartridge has been inserted, thecontroller can use the information stored in memory to look up thecorresponding calibration requirements for ventilator flow measurement,cartridge life, NO setting limits, electrode life and other parametersassociated with the cartridge. The memory device can be transferred fromone controller to another second controller, for example, for transport.The memory device can capture the treatment setting, number of NOmolecules flowed through, number of NO₂ molecules flowed through, alarmlogs, treatment logs and patient history, for example. The benefit ofunderstanding the number of NO and/or NO₂ molecules flowed through ascavenger cartridge is that the service life can be more accuratelydetermined than a time-based method, enabling a scavenger cartridge tobe used more completely before disposal. In one embodiment, the volumeof NO-containing gas flowed through the cartridge is written to thememory device. In some embodiments, the number of plasma discharges thatoccurred during the time the scavenger has been inserted are written tothe cartridge. For scavenger cartridges with more than one scavengerpath, the amount of use of each path is stored independently in thecartridge memory device. In one embodiment, the memory device is used tomark whether or not a cartridge has been inserted into a controller.

Various types of information can be written to the memory device duringthe manufacturing process. For example, the information written to amemory device during cartridge manufacturing can include but is notlimited to information relating to part number, manufacturer ID, date ofmanufacture, expiration date, serial number, lot number, and calibrationconstants for flow measurement, pressure measurement or other sensingcapabilities of the Cartridge. Information written to and read from thememory device during treatment could include but is not limited to countof sparks for a first electrode assembly (A), count of sparks for asecond electrode assembly (B), date of first use, accumulated use time,user group information as Neo (Neonatal), Ped (Pediatric), or Adt(Adult), serial number of a first controller cartridge was used in, andserial number of the last controller cartridge was used in. A cartridgeRFID can store information that includes but is not limited to used/newstate, the last used controller settings, such as desired NO ppm, plasmadischarge rate, and/or plasma duty cycle (for transfer to anothercontroller for transport), alarm history for a patient treatment,patient trending data for FIO₂, SpO₂, NO Level setting, NO levelmeasured, O₂ level measured, NO₂ level measured, user case notes andannotations (for transfer to another controller for transport). Acartridge recycling program can be implemented to responsibly dispose ofcartridges but also to provide data on how the cartridges are used inthe field.

FIG. 143 depicts the hardware architecture of an NO generation anddelivery system with redundancy. The main control board (MCB) 1770 hastwo sub-systems in the form of the User Control and Monitoring (UCM)1772 and the Power Control and Watchdog (PCW) 1774. The UCM 1772 fromtop right counter clock wise connects to a touch panel display assembly1776, system pumps 1778, and antennae 1780 for an RFID subsystem and aWIFI subsystem. There is an I2C bus 1782 that traverses the systemcontroller to the gas sensor pack 1784. This enables the UCM to collectsensor data, water trap data, sensor pack pressure and flow, andprovides for control of the sample line pump.

There is a GSM module and USB Module external to the MCB/UCM, a nursecall function, and multiple speed-controlled cooling fans within thesystem. External to the MCB, enclosure temperature is measured and aspeaker is used for audible alarms. At the bottom of the MCB, there areconnections for up to two GDN boards 1786, 1788. The left side of thedrawing depicts the connectivity to the PCW and the functionality there.There is a service-door-open indication. Two batteries are provided forredundancy that can be charged and drained simultaneously orsequentially. In the event that one battery fails, the system can drawsufficient power from the second battery to continue treatment. There isa DC power in, and AC power in and an indication of switch position.Internal to the PCW module is a piezo buzzer to enables audio alarmsduring a system catastrophe. There are LEDs for status indicators, thepower availability and alarms. A flex circuit containing LEDs (notshown) connects to the MCB and extends up and around the interiorsurface of the handle to illuminate the light bar within the handle toconvey system status.

The internal sensors of the UCM measure ambient light, ambient humidity,orientation, internal temp and internal humidity. There is MMC flashstorage and DRAM. A high speed USB 4 port hub is features as well.

FIG. 144 is an embodiment of a Generate and Delivery NO (GDN) board1790. From Left to right, the GDN receives commands from the UCM such astreatment settings. The GDN controls over the system reactant gas pump.The GDN provides additional power conditioning for the off-board sensorsand system components. The resonant primary circuit connects to thetransformer which in-turn connects to the plasma electrodes. Theoff-board sensors and system components connect to the manifold 1792 toproperly control the flow of the various gases. There is ascavenger/filter cartridge 1794 connected to the manifold 1792 thatremoves contaminants from the system and/or creation of NO. There aresensors in the ventilator cartridge 1796 to measure the flow associatedwith the ventilators and the manual respiration (bagging).

Control Parameters

As explained above, various information relating the system, includinginformation about the product gas, reactant gas, and patient, can beused by the controller as control parameters to control NO production bythe NO generation system.

Plasma parameters that can affect various aspects of NO generation andare controlled by the control parameters, include but are not limitedto:

-   -   Waveform Control Circuit AC Frequency—This is the frequency of        the control signal used to generate the AC current of the        plasma. It is used to tune the resonance of the high voltage        circuit.    -   Waveform Control Circuit AC duty cycle—This is the duty cycle of        the control signal used to generate the AC current of the        plasma. This is used to define the shape of the AC current to        control the energy content of a harmonic of the High Voltage        Circuit.    -   Discharge Pulse—a plasma event, also referred to as “Pulse”    -   Discharge Pulse Frequency—the inverse of the time between        discharges (1/pulse period)    -   Pulse Period—Length of time from the start of one plasma event        to start of the next.    -   Pulse Duty Cycle—Portion of the Discharge Period that the        Electrical Discharge is ON.    -   Plasma Delay—Duration of time between activating high voltage        and actual plasma generation. This is the time required for gas        between the electrodes to ionize and breakdown. This parameter        varies with electrode temperature. By generating bursts of        discharges to keep the electrodes hot, the plasma delay can be        minimized.    -   Discharge Power—the product of potential difference (V) and        current (A) between the electrodes during a discharge.    -   Bursts—groups of closely spaced pulses.    -   Burst count—number of pulses in a burst.    -   Burst Period—Elapsed time between the start of burst events.    -   Burst Duty Cycle—Percent of time during a burst period that        pulses are allowed to occur.

In one embodiment, this parameter is used to generate extremely lowlevels of NO by decreasing duty cycle (i.e. spacing bursts furtherapart).

-   -   Burst Frequency—Number of bursts per second that occur.

NO Generation Algorithm

The NO generation system can vary the rate of NO molecules/time based onone or more input control parameters. Inputs to the NO generationalgorithm can be one or more of the following parameters that can beused to control NO generation/concentration in a product gas produced inthe one or more plasma chambers:

-   -   Concomitant treatment (ventilator, CPAP, ECMO, anesthesia,        manual respiration, etc.) parameters: flow, pressure, gas        temperature, gas humidity. These parameters may be measured by        the NO generation device or sent to the NO generation device by        analog or digital communication.    -   Patient parameters: inspiratory flow, SpO₂, breath detection,        tidal volume, minute volume, expiratory NO₂, etCO₂,    -   Ambient environment parameters: ambient temperature, ambient        pressure, ambient humidity, ambient NO, ambient NO₂    -   Device parameters: Plasma chamber pressure, plasma chamber flow,        plasma chamber temperature, plasma chamber humidity, electrode        temperature, electrode type, electrode gap.    -   NO treatment parameters: target NO concentration, indicated NO        concentration, indicated NO₂ concentration. In some embodiments,        the NO generation algorithm can use humidity and gas composition        sensing of the reactant gas to improve mole flow rate        calculations of the reactant gas and/or inspiratory gas.

Outputs to the NO Generation Algorithm

In some embodiments, the system controls the reactant gas flow throughthe plasma chamber, and all other settings such as plasma frequency,plasma duration, plasma duty cycle, plasma energy, burst count, etc. areconstant.

The table below (Table 1) shows some plasma control algorithms. Variablemeans that the parameter can be adjusted in real time at any point inthe treatment. It will be understood that not all possible combinationsof control parameters are shown in the table.

TABLE 1 Parameter Alg 1 Alg 2 Alg 3 Alg 4 Alg 5 Alg 6 Reactant VariableVariable Variable Variable Constant Constant Gas Flow Discharge ConstantConstant Variable Constant Constant Constant Frequency DischargeConstant Variable Constant Variable Variable — Duty Cycle DischargeConstant Variable Variable Variable Variable Variable Power Pulse DutyConstant Variable Variable Variable Variable Constant Cycle Burst CountConstant — Variable Variable — — Burst Constant — Constant Variable — —Duration Burst Constant — Variable Constant — — Frequency Burst DutyConstant — Variable Variable — — Cycle

In some embodiments, the NO generation system selects plasma controlparameters to minimize NO₂ output. If there is a range of parameterswith equal NO₂ output, then the parameters are selected based onminimizing electrical energy consumption. In some embodiments, plasmacontrol and/or gas flow parameters are selected so that the output ofthe NO generation device is at constant NO concentration so that theperformance is similar to that of an NO take with constant NOconcentration. In some embodiments, plasma control and/or gas flowparameters are selected to that the output NO concentrations of the NOgeneration device follow a predetermined concentration profile overtime.

Inspiratory Flow

In some embodiments, the controller measures the flow of the inspiredair in order to calculate the amount of nitric oxide required to achievethe prescribed NO concentration. This can be achieved using a variety oftechniques, for example, with the use of an inspiratory air flow sensor.In other embodiment, this flow can be measured by measuring a pressurewithin the inspiratory limb as a surrogate to flow, having the userinput the inspiratory flow rate into the controller, and receiving flowrate information through wired or wireless connection from theventilator or other device that is generating/measuring the flow.

Flow may be measured in a variety of ways. In some embodiments, flow ismeasured by a measurement of a pressure drop across a flow restrictionwithin the air flow by a pressure sensor located within the controller.In some embodiments, flow is measured by a measurement of a pressuredrop across a flow restriction within the air flow by a pressure sensorlocated within the disposable cartridge. In some embodiments, flow ismeasured by a measurement via heated wire. In some embodiments, flow ismeasured by a measurement via a heated thermistor. In some embodiments,flow is measured by a thermal mass flow meter that uses a pair oftemperature sensors, such as thermocouples, or resistance temperaturedetectors (RTD).

The system can also include one or more treatment air pumps. Treatmentair consists of a flow of air sufficient for NO generation in asidestream or mainstream application. Treatment air can be a subset ofthe air a patient breathes and is mixed with main flow of air prior toinspiration by the patient.

Air pumps are needed to source atmospheric air and direct it to theplasma chamber. Measurement of the air flow to the plasma chamberensures that the air pumps are functional. In some embodiments, thismeasurement is made with a warmed thermistor, however other flowmeasurement techniques such as differential pressure across a flowresistance would be equally effective. Target air pump speed may be afunction of prescribed NO level, inspiratory air flow rate, airtemperature, air pressure, air humidity, and/or other factors. In anembodiment, set gas flow rates appear in one or more look-up tablesbased on desired NO moles/min desired as well as the variable listedabove.

In some embodiments, gas flow rate measured in the ventilator circuitprovides an input for determining the air pump speed and/or reactant gasflow rate for NO generation. One advantage to this approach is that itperforms well with a patient that breathes spontaneously, ensuring thatthe system increases NO production to match each breath.

The range of air flow rates can vary, for example, from 0 to 15 lpm witha goal of keeping air flows through the plasma chamber at less than orequal to 10% of the mainstream inspiratory air flow. Air pumps may be ofnearly any type, including but not limited to diaphragm, centrifugal,fans, blowers, reciprocating, gear and other designs. In someembodiments, the pump can prevent passive air flow through the pump whenthe pump is off, which will eliminate the nitric oxide generation systempresenting a leak to the ventilator circuit. An example of a pump thatsatisfies this criterion is a diaphragm pump. In some embodiments, apump is used to fill a reservoir at flow rates that vary from 0 to 6 lpmwhile flows exiting the reservoir vary from 0 to 15 lpm. High flow ratesexiting a reservoir may be short duration, depending on the volume ofthe reservoir.

In the event that a pump does not prevent passive gas flow when off, avalve may be placed in series with the pump to block passive air flowfrom the vent circuit to atmosphere. In some embodiments, the valvewould require power to close (open when off) so that any failure of thevalve would not prevent the delivery of nitric oxide to the patient.Passive valves, including but not limited to check valves, duck-billvalves, and cross-slit valves could also work in some applications.

In some embodiments, such as delivery of NO through a nasal cannula, apause in treatment can allow residual NO in the nasal cannula tube toconvert to NO₂. When treatment is resumed, the residual NO₂ would bepushed into the patient. One solution to this is for the air pump tobriefly run in reverse when treatment is resumed, pulling potentiallyNO₂-laden air from the nasal cannula into the scavenger. The air pumpwould run in reverse for sufficient time that the volume of air withinthe nasal cannula has been exchanged with air. At that point, the airpump could switch to forward flow and being plasma activity to deliverNO to the patient.

It should be noted that some types of pumps such as diaphragm pumps arepulsatile, thereby introducing pulsatility into the air flow. Given thatNO production is a function of air density, it follows that higherpressure reactant gas supplies more N₂ and O₂ within the plasma, therebygenerating more NO for a given plasma discharge. When the reactant gaspressure varies, as is the case immediately after a diaphragm pump, NOproduction levels will also vary with pressure. It follows that a higherlevel of NO production consistency can be obtained when pulsatility inthe reactant gas stream has been minimized. There are pneumatic means todiminish pressure pulsatility downstream from a pump, such as using acritical flow orifice, a diaphragm, an accumulator, or a flexible-walledtube such as an elastomeric tube.

In one embodiment, pump pulsatility or other types of pressurefluctuation within the reactant gas is sensed with a pressure sensor,microphone, force sensor, strain gauge, manometer or other type ofpressure sensor and used to determine the timing of plasma activity. Insome embodiments, an NO generation system generates plasma at the sametime in the pump pulse cycle to make NO production more consistent.

The system can also include one or more gas sample valves. Thecontroller can use a manual or software-controlled valve to selectbetween sourcing gas from the sample line and from the atmosphere tofacilitate sourcing clean air for calibration purposes. In someembodiments, a solenoid valve is used to select the source for the gas,however it will be understood that other types of valves can be used toperform this function. In some embodiments, the controller can use avalve to select between sourcing gas from a cartridge or directly fromthe plasma chamber. Gas sourced directly from the plasma chamber canhave NO and NO₂ in it at known amounts for calibration purposes.

The system can also compensate for variance in various ambientconditions, including but not limited to humidity, elevation, pressure,and temperature using ambient pressure measurement and/or spark chamberpressure measurement. For example, humid air is less dense than dry air.However, it is more difficult to ionize and discharge an arc in humidair. The net result of these factors would be converted to a sensitivityfactor. The controller can use sensitivity factors for each ambientcondition, to adjust the NO production in response to current ambientconditions compared with nominal calibration conditions.

A pre-electrode scavenger can be used to make air more consistent forplasma and NO generation. In some embodiments, the pre-electrodescavenger is located within a disposable air filter cartridge and scrubsthe air before it enters the pump (FIG. 49). In some embodiments, thepre-electrode scavenger is located after the pump but before the plasmachamber. In one embodiment, the pre-electrode scavenger material iswithin an air reservoir that serves as an accumulator between the pumpand plasma chamber.

In some embodiments, the system can vary air flow through the sparkchamber while maintaining a constant spark rate. Plasma activity can beconstant (i.e. continuous), periodic, or variable. Achieving a desiredNO concentration profile in a patient flow can be done in a variety ofways, including varying one or more air flows in the presence of sparkactivity. Spark activity can be continuous, intermittent, or variable.In some embodiments, an NO concentration profile can be constant for theentire inspiratory volume. In some embodiments, an NO concentrationprofile can be constant for every nth breath and zero or a lessermagnitude for the rest of breaths.

The system can use a patient treatment parameter as an input to scaleair flow through a spark chamber. For example, inspiratory air flow in aventilator circuit can be used. In one embodiment, reactant gas flow is1/12th of ventilator flow. In another embodiment, reactant gas flowvaries from 1/20^(th) to 1/10^(th) of ventilator flow. The air flow candilute the oxygen concentration in the ventilator circuit, thus thelowest amount of reactant gas flow/ventilation dilution is desirable. Asmaller ratio of air flow to vent flow reduces the dilution of oxygen.Alternatively, gas flow from an oxygen concentrator or from a blendercan be used as a patient treatment parameter input.

Closed-loop control of air flow can be used so that flow through thespark chamber is accurate. Various types of control can be used,including but not limited to control of pressure within a reservoir,control of flow from a pump, control of a variable orifice in thepresence of a pressure head, and analog or digital modulation (e.g. PWM)of a valve with a known orifice/flow restriction in the presence of apressure head.

In some embodiments, a system can be provided where the dilution ofventilator gas flow is limited to enforce a user-defined minimum O₂threshold. For example, when a ventilator is delivering 100% oxygen, atarget patient O₂ concentration of 92% requires diluent flow of lessthan 10% of the ventilator flow when atmospheric air is the diluent.

In order to increase the air flow through the spark chamberconcomitantly with vent flow, the system can be configured to detect theinspiratory pulse in the ventilator circuit as early as possible. Insome embodiments, a ventilator tube (for example, roughly 18″ long) witha flow sensor on the ventilator connection end can be used so that thesystem can detect an inspiratory pulse earlier. In some embodiments,pressure in ventilator inspiratory limb can be measured within the ventcartridge to detect spontaneous breathing such that the NO detectionsystem can detect a breath before the ventilator, thereby enabling thesystem to deliver NO to the leading edge of an inspiratory bolus withoutthe need for a predictive algorithm. In some embodiments, the system cancompare vent flow measurements with NO flow measurements to confirmsynchronous NO flow timing. The comparison can be performed bysubtracting the time of vent peak flow from NO peak flow to calculate aphase offset. In some embodiments, the target delta is offset, in someembodiments it is desirable for the NO pulse to lead the inspiratorypulse, so the offset as defined would be a positive value. In someembodiments, the system uses the timing of a sample (typically a countof 3) of prior inspiratory pulses to predict the timing of a specificinspiratory pulse.

Other Control and Plasma Parameter Considerations

In some embodiments, an open loop with a look-up table based on theprescribed NO concentration indicated by a user is used along with oneor more of the following parameters: cartridge type, ventilator flowrate, ambient temperature, ambient pressure, ambient humidity, measuredNO values in the ventilator inspiratory line, and any other factoraffecting NO production.

Various sensors can also be used in the control of NO production. Insome embodiments, partial feedback control from a single NO sensor thatcan also generate alarms is used. Treatment can only be adjusted (i.e.trimmed) by a limited amount, such as 10%, based on sensor input. Insome embodiments, dual NO sensors can be used, with one sensor beingused for closed-loop control and the other sensor being used for alarmconditions. The two sensors can be compared to each other to detect asensor failure. In some embodiment, a triple NO sensor system can beused for closed-loop control. In the event that one sensor differs fromthe other two, that sensor can be ignored and treatment can continuewith the two remaining sensors. In some embodiments, the NOconcentration alarm threshold is automatically adjusted when a new NOsetting is selected. In some embodiments, the NO alarm setting isdetermined by a tolerance based on a percentage above and a percentagebelow the target value. In some embodiments, the NO alarm setting isdetermined from a look-up table based on the NO target concentration.

Various NO production controls schemes can be employed by the system. Insome embodiments, plasma chamber gas flow rate and one or more controlparameters are used to control NO production. Plasma chamber gas flowrate can be controlled by a pump speed, reservoir chamber pressure,proportional valve setting, or other means. The plasma parameter can berate, duty cycle, switching voltage at the primary transformer winding,or energy. In some embodiments, plasma chamber gas flow rate and plasmaduty cycle are controlled. In some embodiments, plasma chamber gas flowrate and spark energy are controlled. In some embodiments, plasmachamber gas flow rate and plasma frequency are controlled. In someembodiments, plasma gas flow rate is varied to be a function ofrespiratory flow rate variation with breath. In some embodiments, theplasma chamber gas flow rate is a constant proportional fraction (10%)of the inspiratory flow rate. In an embodiment, plasma pulse rate can bevaried to maintain constant NO concentration throughout the respiratorycycle. In an embodiment, air pump speed is held constant and only plasmacontrol parameters are varied to product required NO concentrationsbased on patient inspiratory flow. In one embodiment, plasma parametersare held constant and only plasma gas flow rate is varied. In oneembodiment, plasma parameters are held constant and plasma gas flow rateis controlled to be a fraction of the inspiratory flow rate. In someembodiments, plasma chamber gas flow rate is held constant and plasmaenergy is varied. It will be understood that any combination of these NOproduction schemes can be used.

There can be multiple combinations of plasma chamber gas flow rate andother plasma parameters (for example, pulse rate, pulse width, pulseenergy) that generate a given level of NO molecules. In someembodiments, a plasma parameter for a given NO production level isselected based on minimizing NO₂ levels in the effluent gas. In someembodiments, plasma chamber gas flow rate for a given amount of NOproduction is selected based on minimizing NO₂ levels in the effluentgas. In some embodiments, the combination of plasma gas flow rate andplasma parameter (rate, duty cycle, or energy) are selected based onminimizing NO₂ levels in the product gas.

Spark Energy

In some embodiments, spark energy can be used to control NO production.An increase in spark energy can result in an increase in NO output.Spark energy is a function of high voltage circuit voltage and highvoltage circuit current at the electrode gap. Increasing the dischargepulse frequency and/or shortening the pulse duty cycle has the effect ofincreasing available current in the transformer at the time ofdischarge. Design elements that have an effect on spark energy include:transformer leakage current (minimized), transformer capacitance(minimized by use of Litz wire and keeping wire dimensionally close tothe magnetic core), having a power factor correction unit tuned todeliver resonant alternating current (AC) to the transformer, minimizingtransformer temperature by decreasing wire impedance (Litz wire). Thesystem can also operate such that there is continuous NO production. Insome embodiments, the nitric oxide generation system can operate with apriority for nitric oxide generation. Thus, the system continues togenerate nitric oxide in the event of any single fault. Even when thereis an alarm condition, the system can continue NO generation whilenotifying the user of an issue. The system can be designed withredundancy for several of the critical system elements. Two or more ofthe following system elements may be present to ensure continuousoperation: electrodes, scavenger circuits, air pumps, high voltagecircuits, plasma timing circuits, nitric oxide sensors, and batteries.

In some embodiments, an NO generation device can include a pneumaticloop that continuously circulates NO containing gas and scrubs it sothat it is available for delivery. After the plasma chamber, oxygen andnitrogen concentration remain virtually unchanged from their atmosphericconcentrations of approximately 21% and 78% by volume respectively.Therefore, NO₂ is forming from the moment NO is generated in the plasma.Some of this NO₂ can be chemically removed after the electric NOgenerator before the NO-rich gas is mixed into the inspiratory flow.Depending on the detailed design of the pneumatic circuit, and thedetails of the inspiratory flow rate and NO-therapy, the residence timeof the NO-rich, O₂-rich gas in the volume after chemical NO₂ removal butbefore injection may be excessive. Excessive residence time leads togreater NO₂ formation. This design considers a recirculating loop ofNO-rich gas. The gas is constantly circulating, and only a portion isdiverted to the inspiratory limb. Recirculation limits residence time,so NO₂ formation can be limited. Moreover, gas that returns to the NOsource can be “re-scrubbed” to limit NO₂ accumulation, as explained inmore detail with respect to FIGS. 93-95.

Patients receiving nitric oxide require gradual weaning rather than anabrupt stop, and the system can support weaning a patient in severalways. In some embodiments, the system can provide a weaning reminder tonotify the user that the patient has been at a particular dosage for auser-selected amount of time. In an embodiment, the system can automateweaning based on physiological inputs, including but not limited to SpO₂levels. In this mode, the system would lower the NO dose and monitorpatient response. If the patient does not respond well (SpO₂ levelsdecrease for example) to the decreased dosage of NO, the NO level couldbe increased again. In an embodiment, the system can provide a trendingscreen to show a patient's response to weaning as well as generalpatient history. The trending screen can display various informationabout the patient and the treatment, including but not limited toprescribed NO dose, measured NO levels, SpO₂ levels, FIO₂ levels, andother parameters specific to the treatment or general patient status.

In some embodiments, nitric oxide delivery and generation systemsperform measurement of NO, NO₂, O₂ and other gases from time to time.The gas sensors can be calibrated periodically to ensure adequatemeasurement accuracy.

Altitude Compensation

The density of air at high elevations is less than at lower elevations.It follows that there are fewer O₂ and N₂ molecules between an electrodegap at a higher elevation, so that NO molecules are produced at a slowerrate than at sea level. The reduction in molecules of all kinds betweenthe electrodes at high elevation also decreases the breakdown voltagefor an electrical discharge to occur. In some embodiments, an NOgenerator can measure ambient pressure as an indication of the status ofgas in the plasma chamber. In some embodiments, pressure within theplasma chamber is measured. The controller can alter electricaldischarge activity as a function of plasma chamber pressure to ensureaccurate quantities of NO are generated. In some embodiments, a variableflow restriction downstream of the plasma chamber is used to controlpressure within the plasma chamber. For example, at higher elevations, aproportional valve can be adjusted to restrict flow and increasepressure within the plasma chamber thereby increasing NO output. In someembodiments, changes to the high voltage parameters are not required athigh elevation because the pressure within the plasma chamber ismaintained at a constant level.

Variance in Ambient Conditions

In some embodiments, an NO generation system includes a means ofcompensation for variance in ambient conditions (humidity, elevation,pressure, temperature) since these conditions can affect the number ofNO molecules generated for a given electrical discharge. Compensationcan be in the form of altering one or more of the following parameters:the duration of electrical discharges, the frequency of discharges, thevoltage of discharges, the duty cycle of electrical discharges, thepressure within the plasma chamber, the flow rate through the plasmachamber, the discharge burst count or other parameters known to affectNO production rates. In some embodiments, the NO generation systemmeasures one or more of the following parameters: ambient pressure,plasma chamber pressure, ambient temperature, plasma chambertemperature, ambient humidity, plasma chamber humidity.

Continuous Variation of Flow

Patient respiration can be voluntary or induced by machine. In eithercase, the flow rate is dynamic as a patient inspires. This presents achallenge to an NO generation device to provide a constant concentrationof NO to the patient.

In inline (mainstream) configurations where the plasma occurs within theinspiratory gas, plasma parameters alone can be varied in real time todose the inspiratory gases appropriately. In some embodiments, thecontroller senses a pressure and or flow measurement that serves as thecontrolling input.

In side-stream configurations, plasma is generated in an N₂ and O₂containing gas source that is independent of the patient inspired gas.For example, a side-stream NO generation device sources N₂ andO₂-containing gas from an external source, converts a portion of the gasto NO and introduces that NO-containing gas to a ventilator circuit. Inthis example, the NO generation device must generate a variable amountNO in proportion with ventilator flow in order to achieve constant NOconcentrations in the inspired gas. In one embodiment, the NO generationdevice delivers a constant flow of NO-containing gas to the ventilatorcircuit and only varies one or more plasma control parameters.

Pressure variance within the ventilator circuit presents a resistance tothe introduction of NO-containing gas into the ventilator stream. Insome embodiments, running a pump at a constant rate can result in asituation where no NO is introduced into the ventilator duringinspiration due to the high pressure that occurs during the inspiratorypulse. In some embodiments, a small orifice can be used at the NOinjection location to keep product gas pressure higher than the pressurewithin the ventilator circuit, ensuring that there is always NO flowinto the ventilator circuit.

In some embodiments, reactant gas flow through the NO generation deviceis varied as a function of ventilator flow. In one embodiment, air flowthrough the NO generation device is varied as a linear proportion to theflow rate of the patient inspiratory flow. In one embodiment, the linearproportion is 1-10%, however ratios as high as 20% have beencontemplated.

Varying reactant gas flow continuously in real time through the NOgenerator as a function of an input parameter offers advantages: 1) Thequantity of NO molecules increases with increasing flow through theplasma, thereby increasing NO generation when it is needed, 2) Pressurewithin the NO generation system increases as inspiratory flow pressureincreases, thereby ensuring that product gas continues to flow into theinspiratory flow, 3) Changes in plasma control parameters or notnecessary in order to deliver constant NO concentration to the patient,4) High reactant gas flow rate minimizes the transit delay and residencetime of NO-rich gas in the controller.

The input parameter can be an indication of the patient inspiratorycycle timing and/or flow rate. The sensed parameter could be one or moreof the following: pressure, flow, temperature, strain, acoustic,ultrasonic, optical or other means. The parameter could be senseddirectly by the NO generation device or measured by another device andcommunicated to the NO generation device via wired, wireless, optical,or other means. In one embodiment, Inspiratory flow rate is measured bythe NO generation system. In one embodiment, ventilator flow rate ismeasured by the NO generation system. In one embodiment, a trigger eventis marked by a ventilator and communicated to the NO generation device.In one embodiment, patient chest wall strain and/or diaphragm EMGactivity are communicated to the NO generation device. In oneembodiment, NO generation is controlled based on one or more of an inputof patient inspiration acoustics (microphone measurement), inspiratorycircuit pressure, inspiratory flow temperature (exhaled gases are warm).

NO/NO₂ Ratio Optimization During Generation—Ozone

The ratio of NO₂ to NO generated during an electrical discharge canvary. One of the mechanisms for forming NO₂ is when O₃ combines with NO.O₃ is formed from electrical corona which can occur as electricalpotential builds in the electrodes prior to discharge. The production ofNO is maintained by the control signal from the high voltage controlcircuit. In one embodiment, this consists of a wave made up of ACpulses. The term “wave” refers to the control signal going to thecircuit that drives the primary coil of the high voltage transformer.When the wave is high (during the high part of a pulse), the primarycircuit drives the transformer with AC current. When the wave is low(pulse off), the primary circuit is inactive. In general, the amount ofNO generated is proportional to the percentage of time that the pulsesin this wave are ACTIVE (i.e generating NO). At the start of a pulse,the voltage builds until plasma breakdown across the electrode occurs.This slight delay reduces the time within the pulse that the pulse isactive. If the pulse is relatively short, the voltage build-up could bea significant portion of the pulse and thus significantly reduce theeffective ON time, and thus reduce the production of NO. Hot electrodesionize the gas between them. Thus, a breakdown delay is decreased if thetime between pulses is reduced because the electrodes do not have timeto cool significantly between pulses. In one embodiment, pulses aregrouped close together to reduce the breakdown delay. In one embodiment,space is introduced between groups of pulses to keep the NO productionfrom climbing too high and to maintain the average effective time thatthe wave is active.

In some embodiments, after the initial plasma breakdown, the controlwave voltage may be reduced to maintain the spark at a lower energyuntil the pulse ends. For example, for a 2.5 mm gap, it can require 6-12kV to breakdown the gap and create the plasma, it only requires 500-1000volts to maintain it. Reducing the control voltage reduces the currentin the plasma, and thus the energy, allowing the formation of low energyplasma which enables the production of low doses of NO. A reduction ofthe plasma energy also improves the electrical efficiency of thecontroller.

In some embodiments, the system uses bursts of discharges (a series ofdischarges in rapid succession) to keep electrodes hot, thereby reducingplasma delay in subsequent discharges after the first discharge. In oneembodiment, the system varies the pause between bursts to control NOoutput levels. The pause between bursts also provides time forelectrodes to cool the reactant gas flow. In one method, anti-coronainsulator materials are used on and around the electrodes to decrease O₃formation from corona.

Production of NO per watt can have optimal control parameters. Duringthe development of an NO generation device, optimal plasma parametersare determined and used as defaults for commercial designs. In oneembodiment, the device sweeps some or all of the spark parameters todetermine optimum settings before or during the early stages of atreatment. A capacitive high voltage storage device was not selected forreliability reasons.

Energy optimization and NO₂ minimization often do not coincide. In someembodiments, plasma control parameters are selected to optimizeelectrical efficiency. In some embodiments, plasma control parametersare selected to minimize NO₂ production. In some embodiments, plasmacontrol parameters are selected to optimize a combination of NO₂ levelsand electrical efficiency, recognizing that neither parameter isoptimized.

NO₂ Management

NO oxides in the presence of oxygen and will entirely oxidize into NO₂given sufficient time. NO₂ is unhealthy to breath because it formsnitric acid when it contents moisture, as is found in the lining of thelung. It follows that NO generation systems should minimize the amountof NO₂ delivered to the patient. NO₂ levels are reduced by inclusion ofa scrubber, however additional algorithmic approaches can reduce NO₂delivery further.

In one embodiment, the NO generation system continues to run thereactant gas pump for a period of time after plasma activity ceases.This purges the pneumatic paths and scavenger of the device. Cessationof plasma activity could be when treatment is terminated. Cessation ofplasma activity could also be breath to breath. In one embodiment, theNO generation system can reverse the direction of flow through thescavenger, directing NO₂ to the system exhaust port instead of thepatient. In one embodiment, product gas is exposed to UV light with afrequency in the range of 300 nm to 420 nm to convert NO₂ to NO prior toinjection into an inspiratory stream. In one embodiment, the inspiratorystream is exposed to UV light with a frequency between 300 nm and 420 nmpost NO-injection.

Dose Management

Trim Adjustment

Treatment set-ups for NO delivery vary with patient size (vent tubingdiameter), humidifier type, patient tubing length, auxiliary concomitanttreatments (nebulizers for example) and other variables. It follows,that the transit time from NO generation to the patient will vary inturn which can cause variance in the amount of NO conversion to NO₂.Additional transit time occurs as sample gases travel from the gassampling location in the inspiratory limb to the gas analysis sensors.As a result, the amount of NO indicated by the gas sensors may bedifferent (typically lower) than the amount of NO requested. In oneembodiment, an NO generation device has a trim feature that enables fineadjustments in the NO production to be made so that NO measurements atthe gas sensors match the target NO level. In some embodiments, an NOgeneration device has a trim feature that enables fine adjustments inthe NO production to be made so that measurements at the gas sensors areequal to the target NO concentration+the NO amounts lost due to transitfrom the sample collection point to the sensors.

Manual Trim Adjustment

A manual trim feature enables a User to overcome variances in thepatient set-up that alter the amount of NO delivered to the patient.Increases in NO production using the trim feature will increase both NOand NO₂ production. The trim feature does not alter NO and NO₂ alarmlevels, so that safety features are unchanged. In one embodiment, thetrim feature is presented on a touch screen interface. In oneembodiment, the trim feature is a physical knob.

Automatic Trim Adjustment

In one embodiment, the system uses gas sensor data to automaticallyincrease or decrease NO production to match the target NO delivery levelin a closed-loop fashion. In one embodiment, the automatic trimadjustment is limited to a particular magnitude of adjustment. In oneembodiment, the level of trim adjustment is limited to a set number ofppm of NO. In one embodiment, the level of trim adjustment is limited toa percentage of the target NO level (for example, 10%). In someembodiments, an automatic trim feature compensates for NO losses thatoccur during transit within the sample line so that it is controlling NOconcentration at the sample collection point.

Multiple Doses of NO

In some embodiments, it is possible to use multiple doses of NO toprovide a multi-stage NO therapy. For example, a first dose of NO can beused to dilate a pulmonary vessel or an airway, and a second dose of NOcan be used to sustain dilation. In some embodiments, an NO generationand delivery device delivers a high dose for a set amount of time (1-2minutes for example) before automatically lowering the dose to thetarget dose. In another embodiment, a high dose is delivered for acertain number of breaths (10 for example) before changing to the targetdose. The transition from the high dose to the target dose can be a stepfunction or a continuous decline (linear, logarithmic, etc.). In someembodiments, the high dose is a set value for all patients. In someembodiments, the high dose is a function of the target dose (2 times thetarget dose, for example).

User Interface

In some embodiments, the system can include a user interface (UI) incommunication with the controller and configured to display informationrelating to NO production, treatment settings, alarms, annotations, gasconcentrations, and patient status. The user interface can be configuredto display trending data, the trending data being a time history ofgenerated NO, measured NO, SpO₂, O₂, a respiratory rate, a heart rate,and EKG, or a capnograph. In one embodiment, a light bar is inset withinthe device handle, locating alarm lights high on the enclosure forvisibility. In one embodiment, windows in the side of the handle enablealarm lighting to project out the sides of the handle as well. FIG. 50shows an example of an alarm light bar 762 illuminated flashing red fora high-level alarm. The light bar can be illuminated in other colors,such as flashing yellow for warning, solid green for self-test complete,solid blue for NO delivery active, and flashing white for bag-modeactive. In one embodiment, LEDs for illuminating the light bar arelocated on the edge of the UCM board. In one embodiment, a PCB islocated in the upper portion of the handle to shine light down into thelight bar.

Various types of information can be presented to a user on a graphicaluser interface. In some embodiments, an NO delivery system can provide atrending graph or table that shows the time history of one or more ofthe following: prescribed NO, measured NO, SpO₂, O₂, EKG, respiratoryrate, heart rate, capnography, NO₂. In some embodiments, an NO deliverysystem can have quick NO settings such as 80, 40, 20, 10, 5, 4, 3, 2, 1.In some embodiments, an NO delivery system can display an animated lungthat indicates that treatment is in process. In some embodiments, an NOdelivery system can determine patient respiratory parameters such asrespiratory rate or tidal volume from measured flow in the patientinspiratory limb and present the information on the interface. In someembodiments, the background color of the UI can be changed to indicatetherapy is running. In addition, bezel of the screen has an indicatorstating ‘eNO’ that lights up with treatment is running and NO is beingdelivered to patient.

In some embodiments, an NO generation system can provide the user with areminder of when the patient is ready for the next weaning step todecrease NO levels, as shown in FIGS. 52 and 53. The timer can also beused to remind the user to check patient shortly after initiatingtherapy, i.e. 10 mins to 24 hours, to check whether the patient isresponding to therapy. The reminder can also be used as a reminder toreplace disposable accessories like disk filter periodically based onhospital protocol. When the set time is up the device can remind theuser as an alarm or a notification using visual and/or audible signals.The reminder can be based on time, SpO₂, or other physiologicalvariables.

FIG. 51A depicts an exemplary embodiment of a user interface. As shownin FIG. 51A, the user interface of a clinical screen can be divided into5 main regions: a status panel, a notification center, a treatmentpanel, a gas analysis center, and a control panel. The notificationcenter can present messaging and information related to a patient,system status, and user instructions. A downward pointing chevron underthe notification center can be pressed and dragged downwards to exposeadditional information. Instead of a precise press on chevron, a swipedown gesture anywhere in the ventilator treatment panel can also exposeadditional information. The additional information could include all theactive alarms and troubleshooting instructions for each of activealarms. The user interface allows for scrollable screen by swipe up anddown gestures. Any time a new alarm is active and a UI closes all popups and submenus and returns the user to main clinical home screen, asshown in FIGS. 54 and 55. The status bar displays real time informationsuch as timer status, cumulative treatment time, patient info, batterystatus and battery remaining in percentage, ac power status, wirelessconnection status, date and time. In some embodiments, elapsed time frominitiation of treatment is shown as well. The cumulative treatment timeis the total time of when treatment was given to the patient since thedevice was turned on where as elapsed time is the total time since thelast time treatment was started. It will be understood that variousother types of information can be displayed to a user in status bar andnotification center.

FIG. 51B illustrates an embodiment of the ventilator treatment panel ofthe user interface. As shown in FIG. 51B, the ventilator treatment panelshows an animation to show system activity (for example, a lung image),the prescribed amount of NO (20), means to enter manual mode, scavengercartridge remaining useful life meter (lower left corner), measured gasvalues, alarm limits (15, 25), and treatment setting adjustments (3buttons on lower right corner). The plus sign increments the prescribedamount in increments that are proportional with the value. For example,from 1 to 10 can be incremented in 1 ppm increments, but beyond 10 theincrements are 5 ppm. The minus button decreases the prescribed amountin similar decrements. In some embodiments, the NO target can be changedby touching the NO target value and sliding a finger up or down until anNO target value is changed to the desired value. FIG. 51C depicts howthe center button with a keypad in it pops up a quick setting menu toenable the User to rapidly select the desired NO concentration. When akeypad for NO target or an alarm settings pops up, the ventilatortreatment area can be semi-transparent and active to allow user to seethe current treatment status at all times. In some embodiments, touchingthe large NO target number can also open a quick setting menu, as shownin FIGS. 56 and 57.

An arc, or a radial or linear gauge, on the treatment panel shows therange of possible NO concentrations, highlighting the current range ofoperation. In some embodiments, the scale represented by the arc can beadjusted by patient type, for example 0 to 40 for a neonate and 0 to 80for an adult. A start button can be located at the center of the arc,and can toggle to a pause button when treatment is active. The interfacecan also include a button to enter manual mode. A highlighted region onthe arc depicts the alarm limits/acceptable tolerance around the setconcentration. In the event that NO concentration goes above or belowthis bracket, an alarm is generated. In one embodiment, the userinterface is a touch screen that enables a User to touch the arc in thelocation of the alarm limit they desire. In one embodiment, the User cantouch the screen and drag the alarm limit along the arc to the desiredlevel.

The gas analysis panel can present the current measured values for NO,NO₂ and O₂ as well as set alarm limits. Pressing a gas panel can pop upalarm range settings menu for respective gas to enable user to rapidlychange the alarm range to desired value. The quick settings also allowuser to change the alarm status of each gas measurement to active,inactive or audio indefinitely paused. In some embodiments, the NO leveldisplayed is equal to the NO level measured by the gas analysis sensorsplus the amount of NO lost in transit from the gas sampling point to thesensors. The amount of NO lost, being calculated as a function of NOconcentration, O₂ concentration and transit time from. Transit time is afunction of sample line internal volume (length, ID, etc.) and samplepump flow rate. In some embodiments, the NO₂ level displayed is equal tothe NO₂ level measured minus the amount of NO lost in transit from thegas sampling point to the sensors. The control panel is static andpresent on all pages of the user interface and can include a menu,patient info, screen lock, and alarm silence. The menu enables the userto go back to a menu home page, view deeper menus, and review case data.The lock button lock and unlocks the screen to prevent accidentaltouches. When screen is locked pressing anywhere on screen enables anunlock animation to alert the user that screen needs to be unlocked. Thehome button in any of the sub menu enables the user to go back to themain clinical home screen from any screen. An exemplary user interfacescreen is shown in FIG. 58.

FIG. 51D illustrates an embodiment of the manual mode screen, whichdisplays to the user that the system has manual mode initiated. Thedesired NO concentration is displayed. Plus and minus buttons enable theuser to adjust NO concentration quickly while the key pad button pops upthe quick setting to allow user to manual enter the desired setting, asshown in FIG. 59.

FIG. 51E depicts an embodiment of a trending screen that can displayhistorical NO settings, actual NO measurements, NO₂ measurements, O₂measurements, SPO₂ measurements, user entries/annotations, CO₂(capnography), respiratory rate, EKG, pulse rate and other physiologicaland environmental measurements. The amount of time displayed in thetrending graph can vary, but in an embodiment the graph displays 72hours. In some embodiment, the trend graph can be swiped left to displayhistorical data collected for current therapy beyond the timerepresented in x-axis, as shown in FIG. 60. A user can change theX-axis, for a subset of the 72 hours. The trending screen enables aphysician to see what happened to a patient over a period of time, forexample a weekend. FIG. 21F depicts an embodiment of a trending screendisplaying the trending data in tabular form, which can be swiped up todisplay historical data, as shown in FIG. 61.

FIG. 51G depicts an embodiment of a menu screen. When the menu button ispressed, the user has access to manual ventilation mode button displaysettings, manual HI-calibration, manual low calibration,auto-calibration, settings and defaults. A help feature can also be madeavailable where there a FAQ. A searchable IFU can also be made availablein Help. The entry to clinical and biomed settings can be passwordprotected to restricted or can be programmed to give access to anindividual or group of user IDs. In some embodiments, the settings couldinclude ability for user to generate and customize presets for alarms,timer, alarm limits, NO target defaults, etc. based on patient type orpatient disease state or department. An exemplary user interface screenin shown in FIG. 62.

During normal use, the user interface can be static or animated. Theanimation on the screen can alert the user to the fact that that thesystem is functioning properly. In an embodiment, the animation is inthe form of a lung image with arrows or dots representing NO gasentering the lung. NO gas existing in the lung can also be displayed. Insome embodiments, the lung animation could accurately represent the bpmin real time. In manual mode a bag animation on screen can alert theuser to the fact that the system is in manual mode and the system isfunctional properly. The bag animation could be a flashing animationtoggling between colored bag representing bag filled with gas touncolored bag representing empty bag or an animation showing gradualinflation and deflation of the bag.

The user interface can also display tidal volume of the patient, asmeasured by integrating the gas flow measurements in the ventilator flowpath. To improve the accuracy of the calculation of tidal volume, thesystem can use the measured flow rate within the inspiratory line duringpatient exhalation as an indication of ventilator bias flow.

The user interface can include various displays and features. In someembodiments, a lung animation can be used with drug going down into thelung and back out. For example, the displayed lung can be initiallycolored black on the insides. As a drug enters the lung, shading in thedisplayed lung can change from top to bottom to make the lung a color(such as pink). As the patient exhales, the pink shading retreats andthe displayed lung can become black again. The display can also includean animation of NO flowing through a bag to indicate NO delivery to abag. For example, a gradient can be shown moving from one end to theother of a bag image. The bag can be empty (black) or colored toindicate the presence of a drug.

When a patient is taken off respiratory assistance with an automaticventilator and transitioned to manual ventilation (i.e. bagging), thereis a risk that the NO concentration delivered changes from the firstmode to the next. This could lead to adverse effects to the patient. Oneconcept to prevent a rapid change in NO concentration delivered is foran NO generation system to automatically set the NO concentration formanual respiration to the same level as it was in ventilatorrespiration. The opposite is also applicable, when NO delivery changesfrom bag to ventilator delivery. The system also doesn't allow a user toswitch between modes if no flow is detected in the desired mode.

Scavenger

The scavenger path can vary in size, shape, and design. In someembodiments, a scavenger path with a round profile with about 0.25 inchinside diameter can be used. It will be understood that other smallcross sections can also be used, depending on the gas flow rate. In anexample, standard commercially available scavengers (United FiltrationP/N DIA-BNMB) measures 2 cm in ID, 3 cm in length and has 6 g ofscavenger material. It has a 0.25 inch barb fitting on each end for gasentry and exit. By decreasing the cross-sectional area, it can beensured that all of the scavenger material was contacted by gas, even atlow flow rates. This allowed for a marked improvement in scavengerefficacy, reducing the NO₂ ppm in the exiting flow, and increased thelongevity of the scavenger. Longevity of the scavenger can be determinedby subjecting the scavenger to a simulated clinical scenario until NO₂levels reach a clinically relevant threshold, for example 5 ppm. In someembodiments, the cross-sectional area of the scavenger is kept small,which provides greater control over the path length for gases to traveland improves scavenger efficacy. The benefit of having a relativelysmall cross section is that gas passes with greater velocity, moreactively mixing and contacting scavenger material.

In some embodiments, the system has two independent scavenger paths. Thefirst scavenger path is for ventilator NO delivery and the secondscavenger path is a back-up for ventilator delivery or a manualventilation device.

The scavenger can include one or more paths through the scavengermaterial. Since a gas will take the shortest path, a long scavenger pathwith small cross-sectional area is used rather than a short path withlarge cross-sectional area. In order to package a long scavenger pathinto a more compact space, the scavenger path can have a switch-backdesign, resembling a maze. Many configurations of the scavenger path canbe used, including but not limited to a spiral to the tube for compactpackaging.

The scavenger can be made from a variety of materials. In someembodiments, the scavenger material is soda lime, which is a combinationof sodium hydroxide, potassium hydroxide, and calcium hydroxide. Sodalime is available in multiple physical form factors, including cylindersand half-spheres.

Soda lime is brittle and can fracture during handling. When soda limefractures particles of soda lime can travel through the scavenger pathand clog the filter at the exit. In one embodiment shown in FIG. 63, thescavenger path 770 has multiple particle filters 772 spaced along theflow path to capture soda lime particulate. This design limits theamount of particulate matter that can collect in any one filter.

In some embodiments, soda lime is compounded or mixed with a materialthat increases its toughness while maintains NO₂ absorption. In someembodiments, soda lime is blended with sugar to increase toughness. Insome embodiments, a flexible polymer shell that is permeable to NO₂ isplaced around one or more soda lime particles. In some embodiments, aflexible substrate is coated with soda lime to prevent soda limefracturing. In some embodiments, the flexible substrate is a tube withsoda lime coating the interior wall. In some embodiments, soda limeparticles are embedded in a porous structure (open cell foam). The foamprotects the soda lime from compression and shear while maintain an opengas pathway and ability to collect particles. In some embodiments, sodalime is packaged in a rigid walled tube to protect granular materialfrom crushing. In some embodiments, soda lime pellets are mixed withelastomeric or relatively soft pellets within a volume so that the softpellets protect the soda lime pellets when displacement and/or vibrationis applied. In some embodiments, the gas flow through a bed of soda limeparticles is vertical with respect to gravity so that particles settleto the bottom of a chamber when gas flow rates are sufficiently low ornonexistent.

In some embodiments, the product gas flow path within an NO generationdevice is designed to sequester soda lime particulate to preventparticulate from clogging a filter. In some embodiments, the air flowpath at one or more locations within the scavenger has a sharp turns,typically measuring 90 degrees or more. As air flows around the bend,high mass particles travel to the outside of the turn due to centrifugalforce where they collect. In some embodiments, particles collect in apocket or chamber pneumatically connected to the air path. In anotherembodiment, particles collect on an adhesive surface. In someembodiments, particles embed into an open-cell foam.

It can be important to fill the scavenger path and maintainingcontinuous filling of the path with scavenger material. For example, ifa 2-D path is used and it is oriented in a horizontal plane, thescavenger material can settle to the bottom of the path, leaving anunobstructed gas path above the scavenger material. In an embodiment,the air space at the top of the maze path is filled with a closed-cellfoam or other compressible filler material that is compatible with NO toprevent gas from avoiding the scavenger material. In an embodiment, a2-D path is used with the plane of gas travel oriented in a verticalorientation such that the gas is forced to travel through the scavengermaterial as it travels down below obstructions in the gas path. Thebenefit of this approach is that settling of the scavenger material dueto gravity and vibration from transit does not affect the efficacy ofthe scavenger. In an embodiment, the scavenger path travels in 3 or moredirections so that settling of scavenger material does not introduce agas flow path that avoids travel through scavenger material. In anembodiment, a long, slender scavenger path can also be created byfilling a tube with scavenger material. The tube can be spiraled,wrapped, folded, or otherwise routed as part of a disposable device.Molded-in cylinders or other shapes can be added to the cartridge toprovide a structure for wrapping scavenger tubes to package them in atight space without kinking the tube. Referring to FIG. 64, a cartridgehousing 780 is illustrated with five cylinders 782 for wrappingscavenger tubes. The tubes may be formed from a variety of materials,including elastomeric material such as Tygon, or a more rigid materialsuch as stainless steel or Teflon.

In some embodiments, a scavenger path comprises a 2D switchback path ormaze oriented in a vertical plane to ensure gas contact with scavenger.In an embodiment, a scavenger path comprises a 2D tortuous path orientedin a horizontal plane with impervious filler material at the top toprevent gases from not flowing through the scavenger material. In anembodiment, a scavenger path comprises a path that flows in 3 orthogonaldirections (or additional directions) to ensure that gas flows throughthe scavenger regardless of cartridge orientation. In an embodiment, ascavenger path comprises a tube (for example, a rigid tube or anelastomeric tube) located within a cartridge housing. In someembodiments, a scavenger path has a cross-sectional area less than 0.5cm², which can increase the scavenger life by ensuring that a gascontacts all of the scavenger. In some embodiments, a cartridge can havethe ability to redirect gas flowing in one scavenger path to anotherscavenger path. In some embodiments, the scavenger material iscompressed by a spring so that the scavenger material remains packedafter encountering fracturing and settling due to impact, handling,and/or vibration. In some embodiments, a system can be used that iscapable of generating NO from two or more independent plasmas, sendingNO down two or more independent scavenger paths and merging the NO flowinto one patient airstream.

In some embodiments, the scavenger can include a reusable scavengerhousing that enables the user to remove scavenger material and add newscavenger material. By removing and replacing the scavenger material,this allows the remaining components to stay in place while onlyscavenger material is disposed of at the end of treatment.

Nitric oxide is very chemically reactive, thus the material selectionfor the cartridge and other parts of the system that are exposed to NOis important. In some embodiments, polymers such as polyethylene andpolypropylene are used. Alternative polymers may be used as well. Oneway to protect the polymer is to protectively coat the polymer surfacewith metal, ceramic, glass, or scavenger material to prevent NOreaction. In some embodiments, a scavenger path with walls constructedfrom scavenger material.

Various parameters are used to determine the length of the scavengerpath. In some embodiments, the scavenger path length required to reduceNO₂ concentrations to acceptable levels depends on the initial NO₂concentration, flow rate, scavenger path length, scavenger size,scavenger cross-sectional area, the number of parallel scavenger pats,temperature, and/or pressure. For example, an adult being treated with aface mask, receiving 60 lpm of air with a 40 ppm NO would require two,¼″ ID, roughly 70 cm long scavenger paths flowing at 2 lpm with 300 ppmNO in order to last 1 week. On the other hand, neonatal patientsbreathing 20 ppm at 0.5 lpm, require only a 6 cm length of ¼″ ID tubingfor a scavenger that lasts at least one week. Thus, an array ofscavengers can be produced that match the flow rate, NO concentration,and duration requirements of the users.

In some embodiments, a single cartridge can have multiple scavengerpaths with varying length. For example, the cartridge can include ascavenger path with a long path for primary adult applications and ascavenger path with a shorter path for manually ventilating the patientand a back-up for the primary NO generation circuit. The back-up pathcould also be applied to manual ventilation.

In some embodiments, a cartridge can include multiple scavenger pathswith each path having molded-in gates blocking air flow into and out ofthem. Depending on the application that the cartridge is intended for,tabs in the injection molded part are broken out during manufacturing topermit gas to flow through particular scavenger paths.

A scavenger path for manual ventilation can also serve as a back-upcircuit for ventilator NO delivery if there is a failure in any part ofthe ventilator NO circuit. A selector valve enables the user to choosebetween manual mode and ventilator mode for the second circuit.Actuation of the valve can be manual, automatic, or software-controlled.For manual action, levers, rotational knobs, push-pull valves, slidingcontrols, or any other manual mechanism can be used. Software controlledoptions involve solenoid actuation of the valve either physicallyengaging a mechanism on the cartridge or applying an electromagneticforce to an iron slug within the cartridge valve mechanism. In someembodiments, a manual/ventilator selector can be biased towardsventilator support. For example, the selector can only remain in themanual position when an actual manual ventilation device is connected tothe system. In an embodiment, an optical sensor within the controllercan detect the position of the selector and display to the user thatmanual mode has been enabled on a screen or display. Enabling the manualventilation device circuit to also support ventilator function preventsthe need for a third scavenger path in order to provide both redundantventilator support and a manual feature.

The cartridge can include one or more valves at the exit point of thescavenger paths to prevent ventilator circuit contents from entering thescavenger. The valves can be active (such as a solenoid-actuated valve)or passive (such as a duck-bill valve). It will be understood that anytype of valve or other connection can be used at the exit point of thescavenger path to prevent back flow from the ventilator circuitconnected to the cartridge.

One or more outlet filters can be positioned between the scavengermaterial and the spark chamber to prevent migration of scavengermaterial into the spark chamber. A filter can also be positioned betweenthe scavenger and the ventilator circuit to prevent migration ofscavenger material into the ventilator circuit.

Under certain conditions, NO₂ can be converted back into NO. In oneembodiment, the NO generation device exposes NO+air to a heatedmolybdenum feature that catalyzes the NO₂ to NO conversion. In anotherembodiment, NO₂-containing gas is exposed to a heated metal carbidesurface that converts NO₂ back into NO. In another embodiment, a UVlight source with approximately 380 nm wavelength is used to convert NO₂in the gas stream back into NO. In another embodiment, plasma intensityand exposure length is sufficient to convert all oxygen in an air sampleto NO, thereby leaving trace amounts of oxygen to oxidize the NO. Insome embodiments, that converts a high proportion of available oxygen toNO, it is possible that a scavenger to remove NO₂ may not be required ifinitial NO₂ generation levels are sufficiently low.

Pneumatic Design

An NO generation system includes various tubes and manifolds to routereactant and product gases through the system. In one embodiment, asingle manifold provides the pneumatic routing for one or more of thefollowing pneumatic features: Air reservoir, Reservoir pressuremeasurement, proportional valve (i.e. flow controller), reactant gasflow measurement, the plasma chamber, electrode assembly mountinginterface, plasma chamber pressure sensor mounting, Flow directormounting, bleed valve mounting, routing from plasma paths to gasanalysis sensors, routing of product gas to a scavenger path, routing ofproduct gas through a flow director that selects between bag andventilator, routing of product gas to a ventilator cartridge, etc.

In some embodiments, the pneumatic pathways handled by more than onemanifold. In one embodiment, there is a manifold for each redundantpathway.

In some embodiments, there are three scavenger paths: a first ventilatorpath, a second ventilator path, and a manual ventilation (bag circuit)path.

In some embodiments, the pneumatic path is split sequentially, withsmaller manifolds of reduced scope handle the reactant and product gasesin series. In one embodiment, one manifold handles one or more of thefollowing: reactant gas reservoir pressure, proportional orificemounting, reactant gas flow rate measurement, plasma chamber pressure.In some embodiments, a manifold functions as part of the air reservoirhousing; as an endcap, plug, or the air reservoir housing itself, forexample.

In one embodiment, the electrode assembly includes a manifold with areactant gas inlet and product gas outlet. In one embodiment, themanifold is metallic to provide electromagnetic shielding. The electrodeassembly/manifold can be replaced as a unit by the User as part ofroutine service. One design philosophy is to route gases to theelectrodes rather than route electricity to the electrodes. This isbecause gas is easily routed within a system using tubing. Electricityis easy to route too with wires, however the high voltage required forplasma generation generates EMI. Thus, electrical conductor lengthshould be minimized. In one embodiment, the plasma chamber is locatedwithin a faraday cage with gas paths running into and out of the faradaycage. In one embodiment, the electrode assembly/manifold resides in thesame faraday cage as the high voltage circuit and electrical conductorsfrom high voltage circuit to electrode assembly.

In one embodiment, a single manifold handles the pneumatic passages andconnections for the following features: plasma chamber pressuremeasurement, proportional valve for altitude compensation, bleed valvesfor shunting flow to gas analysis sensors, flow director(s) fordirecting product gases to sensors, flow director(s) for routing productgases to specific treatment paths (ventilator treatment vs. manual bagventilation, for example), routing gases to a scavenger path, routinggases from a scavenger path to a NO injection path, routing gases to anNO injector, routing gases to a vent cartridge, etc.

FIGS. 65-68 illustrate various embodiments of pneumatic circuits.

FIG. 65 depicts an exemplary pneumatic design 790 for an NO generationand delivery system. In the upper left of the diagram, sample gases 792originating in the treatment circuit (lower right of the figure labeled‘A’) enter the system through a filter 794 and travel through a watertrap 796. In some embodiments, this filter 794 is disposable so thatuser can replace it as needed when it clogs. An additional filter 798after the water trap 796 protects the gas analysis sensors forcontaminants. Sample gases then flow through a pump 800 and then througha fixed orifice 802 that limits the gas flow rate through the sensorsand diminishes pulsatility in the sample gas flow. Gas then flowsthrough Nafion tubing 804 to add humidity to the sample from theatmosphere in the event that sample gases are very dry. Next, the samplegas flows through one or more gas analysis sensors. Sensors 806, 808,810 for NO, NO₂ and O₂ are shown. A differential pressure sensor shownon the left side of the sensor manifold block is used to measure theflow rate through the gas sensor manifold 812. This flow rate can beused to ensure that the sample pump is functioning. An absolute pressuresensor near the end (bottom) of the sensor manifold is used to measureatmospheric pressure. Gases exit the sensor manifold and flow through aT-fitting, where one leg is connected to atmospheric pressure and theother leg is connected to an external port in the device. The first legis connected to atmosphere to prevent hospital vacuum from affecting theflow rate through the gas sensor manifold and potentially affectingpatient treatment. The external port can be connected to hospital vacuumor just vented to atmosphere.

Moving to the right in FIG. 65, at the top of the diagram there is aninlet 814 to receive reactant gas into the system. In some embodiments,this is a 22 mm medical air connection. Incoming reactant gas flowsthrough a filter 816 to remove particulate then bifurcates into twoparallel NO generation paths. Each path consists of a pump 818 a, 818 b,a reservoir 820 a, 820 b, a reservoir pressure sensor 822 a, 822 b, aproportional flow valve 824 a, 824 b, a fixed orifice, a plasma chamberpressure sensor 826 a, 826 b, and a plasma chamber 828 a, 828 b. Afterthe plasma chamber 828 a, 828 b, each flow path has a flow director 830a, 830 b that can direct gases to either the gas sensor manifold 812 ortowards the patient inspiratory air. These side paths to the gas sensormanifold 812 enable a system to evaluate the gas produced and/orredirect gases within the plasma chamber away from the patient. Afterthe gas analysis side paths, one of the gas paths utilizes a flowdirector 832 to select whether product gases will flow to a ventilatorcircuit (B in the figure) or to a manual bag outlet (C in the figure).Gases then flow through three parallel scrubber passages in a disposablecartridge 833. The scrubber passages consist of a filter, scrubbermaterial, a second filter and a one-way valve. The one-way valve ensuresthat pressures and materials outside of the system do not enter thecartridge and controller.

In the lower right corner of FIG. 65, a treatment setup is depicted. Ina ventilator circuit 834, inspiratory gases exit the ventilator andenter a ventilator cartridge 836. The gases flow through two flowsensors 838, 840. In some embodiments, the flow sensors measurepressure, humidity and temperature in addition to flow. NO-containingproduct gas is merged with the inspiratory flow after the flow sensors.Inspiratory flow continues through a HEPA filter 842, a humidifier 844and on to a “T” fitting 846, where sample gases are pulled, then on tothe patient.

Also shown in the lower right corner of FIG. 65 is a manual baggingcircuit 848. Inspiratory gases are sourced from a blender/walloutlet/cylinder 850 and enter the ventilator cartridge 836. Flow ismeasured within the ventilator cartridge 836 prior to addingNO-containing gas. Gases flow through an optional humidifier 852 and onto a “T” fitting 854 where sample gases are pulled and then on to thepatient.

The system depicted in FIG. 66 is similar to the system depicted in FIG.65 with the exception that a first flow director 860 within thesecondary NO production line selects between flow to the inspiratorylimb and flow to manual respiration/gas sensors, then a second flowdirector 862 selects between flow to the manual bagging circuit and gassensor manifold. One advantage to this configuration is that the flowrestriction of the primary and secondary NO generation lines areidentical. Another feature of this system is a valve at the entry of thegas sensor manifold from the shunt lines can be actuated in combinationwith the flow director valves to create a closed volume that can betested for leaks during a system self-test. The closed volume includespneumatic pathways between the pump and the gas sensor manifold,including the plasma chamber.

FIG. 66. also depicts an embodiment of the reusable portion of thesystem where the manifold is divided into an upper manifold 864, a lowermanifold 866, and replaceable plasma chambers 868 a, 868 b. Separatingthe functions of a manifold into multiple manifolds facilitates manifoldfabrication and eliminates and or minimizes the need for gaskets andplugs which could present a leak in the system. The upper manifold 864is near or part of the reservoir. In one embodiment, the manifold servesas an end-cap to a tubular reservoir. In another embodiment, thereservoir is a volume within the upper manifold. The lower manifold 866houses removable plasma chambers and directs gases to the scavengercartridge 833. In this embodiment, the scavenger cartridge pneumaticallyconnects directly to the ventilator cartridge for reduced NO transittime and reduced pneumatic connections. FIG. 66 depicts a system withouta HEPA filter at the exit of the NO generation system.

FIG. 67 depicts a system embodiment that largely similar to the systemsdepicted in FIG. 65 and FIG. 66. One difference is in how gas for sensoranalysis is redirected. Sample gases from the primary pathway areredirected with a flow director while gases from the secondary pathwayflow through a valve within the gas sensor pathway. This design offers abenefit in that the flow restriction for the primary and secondary flowpaths will be identical thereby decreasing variance in performancebetween the redundant NO generation pathways. Another unique feature ofthis system is that it has no reservoirs and relies solely on pressuregenerated in the line between pump and proportional valve. Generally,this is a small volume making this design most applicable to neonatesand patients with low NO pulsatility.

FIG. 68 provides additional detail of a lower manifold. Reactant gasenters the manifold through a gas inlet 882 in the top. The gas passesthrough the wall of an electrode manifold 884 and into a groove on theoutside of an electrode block 886. The groove is sealed to a bore withinelectrode manifold using O-rings 888. The groove exists around thecircumference of the electrode block to prevent a blind passageway thatcould hold stagnant gas flow that could turn into NO₂. Gas flows fromthe groove into the void within the electrode block that serves as theplasma chamber. An electrode assembly mates with the electrode block toseal the chamber with an O-ring seal. The electrode block is indexed sothat it only enters the electrode block in one orientation. Afterpassing through the plasma, product gas exits through a hole in wall ofthe electrode block into a second circumferential groove. Gas exits thegroove into the electrode manifold and then into the diverter manifoldwhere it passes through a flow-diverters as described above. Theelectrode manifold is fastened to the diverter manifold with threadedfasteners and O-rings provide seal for each pneumatic connection.

As mentioned before, the electrode block seals to the electrode manifoldwith three O-rings. The electrode block can be made from either polymeror metal. In one embodiment, it is made from aluminum, owing to its highthermal conductivity to aid in cooling. Cooling fins on the closed endof the electrode block provide additional surface area to aid in removalof heat form the plasma chamber to the convective cooling air within thedevice enclosure. A removal feature on the end of the electrode blockconsists of a wire form that can be grasped with a finger and pulled toremove the electrode block from the electrode manifold. One benefit tothis design is that the electrode block is replaceable in the event thatit is damaged in use or receives sufficient sputtered materials thatelectrode activity is affected. The electrode block is fastened to theelectrode manifold with screws, a clamp, or some other feature. In oneembodiment, no tools are required to remove the electrode block. Onebenefit of the embodiment depicted in FIG. 92 is that the electrodeassembly can be removed from an access panel in the back of the NOgeneration device by removing the electrode block, replacing theelectrode assembly and re-inserting the electrode block.

On the far side of FIG. 68, an insulative boot 896 is shown to preventforeign materials from shorting the electrode assembly. High voltage isapplied to the center electrode of the electrode assembly by means of anelectrical contact. An electrode return connection 898 contacts theground shell of an electrode assembly to complete the high voltagecircuit.

Introduction of NO Flow to an Inspiratory Flow

NO Injection into Inspiratory Stream

An NO generation system requires a period of time to sense inspiratoryflow, adjust NO generation parameters, generate NO, scrub for NO₂ anddeliver NO to an inspiratory stream. This reaction time delay creates aphase offset between NO demand and NO delivery. If NO delivery lagsdemand, the concentration within the inspiratory stream can be low atthe beginning of an inspiratory pulse and high at the end of aninspiratory pulse.

In some embodiments, NO is introduced to the inspiratory flow as a jetwith higher velocity than the prevailing inspiratory flow. This enablesthe NO entering the inspiratory flow to offset the phase delay and“catch up to” the inspiratory flow.

For example, a bolus of NO intended to dose a bolus of inspiratory aircan be entered after the inspiratory bolus has passed the NO injector,but can catch up with the inspiratory bolus by having a greater rate ofspeed.

In some embodiments, NO flow is injected through a small diameter tube,concentric with the tube conducting the inspiratory air flow. The smallarea increases the speed of NO-rich product gas as it enters theinspiratory flow. In some embodiments, the NO flow rate selected isbased on the lag time of the system. A proportional valve is one way ofadjusting the NO flow. In some embodiments, an axis-aligned jet that issignificantly smaller than the delivery tube to create a jet of NO tomake up for system lag with the objective to create a well-mixedcontrolled concentration.

NO Injection

Pressure within an inspiratory circuit varies. An NO generation devicegenerates product gases at a pressure greater than the pressure withinan inspiratory circuit for there to be flow from the NO generationdevice to the inspiratory circuit. In one embodiment, a large andresponsive pump is used to vary gas pressure and flow, as needed, toensure forward flow of NO into an inspiratory stream. In anotherembodiment, a smaller pump is used to fill an air reservoir to apressure that is higher than within the inspiratory circuit. The volumeof the reservoir is selected based on the inspiratory circuit maximumpressure and maximum NO bolus volume to be required. In this reservoirapproach, the system can deliver high flow and high pressure for a briefamount of time that is sufficient for dosing a bolus of inspiratorygases with NO. Between breaths, the air reservoir is recharged so thatit is ready to dose a subsequent inspiratory bolus.

Owing to the fact that NO has a half-life within the physiology thatlasts longer than a breath, it is not necessary to dose every breath inorder to maintain the desired physiological response. In one embodiment,the NO generation device doses a subset of inspirations. In oneembodiment, NO delivery is set to every other breath. In one embodiment,NO delivery is based on delivering a set number of NO molecules per unittime.

In some embodiments, the NO generation system increases gas pressureupstream of the NO injector and releases a pulse of gas at a specifictime in the inspiratory cycle. In one embodiment, the high-pressure gasis stored within the plasma chamber prior to release.

In some embodiments, high-pressure reactant gas is stored within areservoir located before the plasma chamber. In one embodiment, a meansof flow control is located between the air reservoir and plasma chamberto vary the flow of gas through the plasma chamber. In anotherembodiment, a means of flow control is located after the plasma chamberso that the plasma chamber is at the same pressure as the air reservoir.

In one embodiment, a gas reservoir containing product gas is locatedafter the plasma chamber. A means of flow control (proportional valvefor example) is located between the gas reservoir and NO injector.

The release of pressure can be in response to a sensed inspiratoryevent, in anticipation of an inspiratory event based on the timing ofprior events, based on measurement of a physiologic parameter, based ona trigger signal from a peripheral device (ventilator for example),based on a data stream from a peripheral device.

By adjusting the pressure upstream of the NO injector, the system canmodulate the flow rate of the NO gas that enters the inspiratory stream.

NO Recirculation

In some embodiments of inhaled nitric oxide therapy systems, thepneumatic pathway conducts gas in a single direction from the NO source(i.e. tank or generation unit) to the point where the NO-rich gas isinjected into the flow in the inspiratory circuit (FIG. 69).

In some embodiments, recirculation of gas between the NO source 900 andthe point of injection 902 can be achieved (FIG. 69). This can be usedwith all types of NO generation systems described herein, includingambulatory systems and acute applications, for example, with a remoteNO-injector.

At standard temperature and pressure, nitric oxide reacts with theoxygen to form nitrogen dioxide (NO₂). NO₂ is a toxic pollutant to whichhuman exposure should be limited. The rate of oxidation of NO is therate of formation of NO₂. The reaction rate increases when the NOconcentration is higher, or the oxygen concentration is higher. Thereaction is not very sensitive to temperature near standard temperatureand pressure. During inhaled NO treatment, it is necessary to maintain aconstant concentration of inhaled NO, while minimally diluting theinspiratory flow. Therefore, the NO source is typically a reasonablyhigh concentration (˜500-1000 ppm). If the NO source is a tank ofcompressed gas, and the balance gas is an inert species such asnitrogen, the only significant NO₂ formation occurs in the inspiratorycircuit after the NO-rich gas is mixed in the correct proportion withthe inspiratory flow to achieve the desired dose concentration.

In some embodiments, an electric arc is used to generate nitric oxidefrom ambient air. The nitric oxide (NO) is present in concentration onthe order of 50-5000 ppm depending on the desired dose and inspiratoryflow. However, leftover oxygen and nitrogen remain virtually unchangedfrom their atmospheric concentrations of approximately 21% and 78%respectively. Therefore, NO₂ is forming from the moment NO is generatedin the arc. Some of this NO₂ can be chemically removed after theelectric NO generator before the NO-rich gas is mixed into theinspiratory flow.

Depending on the detailed design of the pneumatic circuit, and thedetails of the inspiratory flow rate and NO-therapy, the residence timeof the NO-rich, O₂-rich gas in the volume after chemical NO₂ removal butbefore injection may be excessive. Excessive residence time leads togreater NO₂ formation.

In some embodiments, there is a recirculating loop of NO-rich gas. Thegas is constantly circulating, and only a portion is diverted to theinspiratory limb. Recirculation limits residence time, so NO₂ formationcan be limited. Moreover, gas that returns to the NO source can be“re-scrubbed” so to limit NO₂ accumulation.

FIG. 70 illustrates an embodiment of a recirculating loop 910 thatcontinuously removes NO₂ from stores NO-containing gas. A valve opens toinject NO containing gases as directed by the NO generator 912. In someembodiments, the valve opens open patient inspiration.

FIG. 71 illustrates an embodiment of a system where recirculated gas 920flows back through the NO generator 922. This is acceptable because onlya fraction of N₂ and O₂ is converted to NO in the plasma chamber. Thus,additional NO can be generated from the same air.

The flow of NO-rich gas can be directed to the inspiratory limb byclosing the injection valve on the return leg, otherwise NO-rich gas iscontinuously recirculating in the loop.

Self-Test (Calibration)

There are various approaches that can be used to ensure that the NOgeneration system is functioning as expected, ensure that the gassensors are functioning as expected, and/or calibrate the system. Itwill be understood that calibration and self-testing areinterchangeable, and in some embodiments refer to testing NO productionand sensor responses. Some of these approaches can significantlydecrease the time and complexity of calibration. In some embodiments, acalibration cartridge is used, and in some embodiments, a calibrationgas shunt internal to the therapy controller device is used. Bothembodiments take advantage of the fact that a controlled plasmagenerates known quantities of NO. The plasma is controlled by takinginto account one or more of the following: ambient air pressure, ambienttemperature, humidity, spark rate, spark duty cycle, air flow rate. Itwill be understood that other factors can also be considered whencontrolling plasma and calibrating the system. The calibrationapproaches described here-in can provide up to a 70% time savings due toa decrease in user involvement and the ability to check NO and NO₂sensor function as well as gas production simultaneously.

In some embodiments shown in FIG. 72, a calibration cartridge 930directs output NO/NO₂-containing gas flow from a plasma chamber 936through a shunt 934 to the sensor chamber input prior to scavenging forNO₂. By controlling plasma activity according to environmentalconditions and desired NO and NO₂ concentration levels, the sensors canbe exposed to known high or low values for sensor calibration. Althoughthe accuracy of this approach is not at the same level as a calibrationwith traceable calibration gas, this test can detect system performanceissues with minimal user effort. FIG. 72 illustrates an embodiment of acalibration cartridge 930. The calibration cartridge 930 can include anRFID chip 932, a bar-code, and a unique mechanical interface or othermeans of automatic identification by the controller. The system canautomatically enter calibration mode when a calibration cartridge 930has been inserted and detected. The RFID chip 932 can also includecalibration constants for a specific cartridge, if cartridge tocartridge variance is sufficient to warrant this level of control. Itwill be understood that other identification mechanisms can be used inplace of or in conjunction with the RFID chip, including but not limitedto a 2D bar code.

In some embodiments, the calibration cartridge also includes additionalfeatures, such as a carbon filter to remove NO from ambient air, whichcan assure that zero levels for low calibration do not have an offsetdue to environment NO levels. The calibration cartridge includes a gasconnection, and in an embodiment it has a gas connection on the frontsurface for the addition of O₂, NO, or NO₂ gas for manual calibrationwith an external source of calibration gas. The gas connection iscontrolled by a valve, stop-cock, solenoid, or other means. In someembodiments, the gas connection valve can be in the same location as themanual/ventilator selector on a standard cartridge for increased ease ofuse.

In some embodiments, in a system that has electrodes located within thecontroller, output gases from the plasma chamber can be directed to thesample chamber through a pathway entirely within the controller, notpassing through a cartridge (FIGS. 65, 66, 67, 68). This allows forcalibration of high or low values at any time without requiringadditional equipment in the form of a calibration cartridge orcompressed gas cylinder. One or more shunts from a plasma chamber outputof a plasma chamber to the gas sensor chamber can be controlled by asoftware-controlled valve, manual valve, pump, or any other means offlow control. In some embodiments, the response of the gas sensors andNO production of one NO generation path can be checked simultaneouslywhile another NO generation path is delivery NO to a patient.

A sensor response test (high calibration) can be performed by generatingplasma at a rate that produces a known amount of NO and NO₂. Lowcalibration can be performed by stopping the plasma generation andexposing the sensors to ambient air. Alternatively, low calibration forNO and NO₂ can be performed at the same time as high calibration for O₂since O₂ calibration gas does not contain NO or NO₂.

Sample Lines

The system also includes one or more sample lines. The sample line canbe a disposable component that is used to convey gas samples from theventilator inspiratory limb to the gas analysis sensors. In someembodiments, the sample line is a tube with one or more lumens. Thesample line can include additional features that can be incorporatedinto the design to facilitate use, plan for humidity effects, andaccommodate viscous materials that could enter the sample line. In anembodiment, a sample line includes a fitting for installation of thesample line into a ventilator circuit. For example, the sample line caninclude a “T”-fitting at the patient-end to facilitate rapidinstallation into a ventilator circuit. The “T” fitting can be sized forthe ventilator tubing size expected, such as 22 mm for adults. In anembodiment, the gas sample is pulled from the center of the ventilatorflow instead of the wall of the “T” fitting, thereby decreasing thepotential for moisture or other materials within the ventilator linefrom entering the sample line.

Between the “T” fitting and the cartridge/controller runs a sample linetube. The sample line tube can have a variety of shaped and sizes. In anembodiment, the tube measures 10′ (3 m) in length, but other lengths canbe used. In general, a shortest possible length of the tube is best tominimize NO to NO₂ conversion in the sample line and provide the gasanalysis sensors with a timely sample.

The sample line tube connects to a sample line filter. The sample linefilter can have a variety of shapes and sizes. In an embodiment, thesample line filter is a 0.2 μm, hydrophilic, 50 mm diameter filter withLuer connectors on either end. The filter is hydrophilic so thatmoisture in the sample line passes through to the water trap. Otherdiameters are possible and will directly relate to how long a filter canbe used before it clogs and requires replacement. Any type of connectorscan be used in place of the Luer connections, including but not limitedto other small-bore push/pull and threaded connectors, as long as theymake an air tight seal.

In some embodiments, the sample line can include a dehumidificationsection, which can have many forms. For example, it can be a length ofNafion tubing to help convey humidity from the gas sample to the ambientsurroundings. In an embodiment, the sample line can have a triple lumentube, where one lumen is used to pull the sample gases from the patient.The other two lumens can be used to measure the patient inspiratory flowrate. The sample line with three lumens allows for gas samples and flowrates to be measured in the sample place, providing gas sample and flowdata that are synchronized in time. This approach also can decreasecomplexity within the cartridge.

Water Trap

The water trap, as noted above, fills with condensate and othermaterials from the inspiratory line. In some embodiments, the user canbe notified that the water trap is nearly full before there is no flowthrough the water trap. The fluid level in the water trap can bedetected in a variety of ways, including but not limited to optically,ultrasonically, conductively and capacitively. The water trap can beassociated with one or more sensors, and a water trap 942 can be locatedwithin a sensor pack 940 (as shown in FIG. 73) or within the controller.In some embodiments, the water trap can be located near a heat source tohelp evaporate water trap contents out of the reservoir. In someembodiments, a dye can be added to the water trap to increase theopacity of fluid that collects within the water trap, making it easierto detect optically.

The water trap may be used with a portable NO generator that couldexperience lateral accelerations from motion and/or orientation withrespect to gravity. In one embodiment, an open-cell foam or sponge isplaced in the bottom of the water trap to prevent splashing or migrationof fluid. In another embodiment, super-adsorbent polymer (SodiumPolyacrylate) is placed in the reservoir to control migration of fluidsfrom the water trap reservoir. In one embodiment, the super-adsorbentpolymer is housed within a package to prevent migration. In oneembodiment, the package is a gel-pack. In another embodiment, thepackage is a perforated pouch.

In some embodiments, the water trap consists of a 1 micron hydrophilicfilter, a water separator, a reservoir and a 0.22 micron sensorprotection filter. In one embodiment, the reservoir is separable fromthe water separator for ease in emptying. In one embodiment, there is asyringe-activated small-bore fitting on the reservoir for draining thereservoir. In another embodiment, a stop-cock or othermanually-activated valve is connected to the water reservoir for ease indraining. In one embodiment, the water separator consists of acoalescing filter. The coalescing filter may be wrapped in a hydrophobicfilter material to protect it from fluid splashes from the reservoir. Inanother embodiment, the water separator uses centripetal acceleration toseparate water droplets from the air by flowing the air around a turn ina flow path. In one embodiment, there are baffles within the reservoirto prevent fluid splashes contacting a coalescing filter. Obstruction ofeither filter can be detected by sample line pressure and/or sample lineflow.

As explained in more detail below, a cartridge can include a water trapthat has a hydrophobic barrier that sample gases pass through. Liquidwater can collect on the bottom of the water trap while sample gaseswith water vapor pass through. The water trap can hold various volumesof liquid. In an embodiment, the water traps can measure roughly 10 mlin volume, but this volume can require draining and/or replacementmultiple times within a treatment. In an embodiment, the water trap canmeasure a volume that holds enough liquid such that the water trap doesnot need to be drained. For example, the water trap can measure 60 ml involume so that the water trap does not require draining under normalcircumstances.

In some embodiments, the water trap is located near a warm area of thecontroller, such as the high voltage power supplies of the electrodeassembly. The heat from the controller can warm the water trap contentsand can drive the liquid contents of the water trap into vapor form suchthat the vapor can exit the controller through a gas sensor chamber.

In some embodiments, the level of liquid in the water trap can bevisible to the user, for example, when viewed from the front of thecontroller. The visibility of the water trap contents can facilitatetrouble shooting when an alarm relating to the water trap is generated,for example, by a gas analysis sensor generating an air flow alarm.Fluid level within the water trap can be detected in a variety of ways,including optically, ultrasonically, conductively, and with other means.In some embodiments, detecting a fluid level in the water trap isachieved by detecting a drop in pressure within the gas sensor chamber.

In the event that the water trap is full or needs to be drained, theuser can drain the water trap with a valve connected to the water trap.In an embodiment, a syringe-activated Luer fitting can be used, but itcan be understood that any kind of stopcock, spout, or valve can be usedto drain the water trap. In some embodiments, the controller canautomatically empty the water trap via a liquid pump. The pump cantransfer the water trap contents to a drain or larger reservoir.

Water traps fill during treatment. In some embodiments, the water trapis removable so that a reservoir can be drained of water. In someembodiments, there is an outlet in the reservoir to enable draining ofthe water trap without removal of the reservoir from the system. Theoutlet may have a small-bore connector like a luer fitting or barbfitting. Fluid flow through the outlet can be controlled by a stop cock,tubing clamp, syringe activated valve, etc. In some embodiments, thelevel of fluid in the water trap is measured by the system. This enablesthe system to alert the user about an impending full water trapcondition before the water trap is completely full. The system can alsomeasure gas flow through the sensor bench. In the event that the gasflow diminishes, the system generates an alarm for the user to check thewater trap.

Gas Sensors

Various mechanisms can be used to measure the concentration of the gasesin the system. Oxygen sensors can often last longer than NO and NO₂sensors. In addition, the amount of O₂ in the ventilator circuit doesnot significantly change between the time gas leaves the NO device andreaches the patient. Thus, in some embodiments an O₂ sensor can belocated in the cartridge or controller, instead of the sensor pack. Thiskeeps sample gas for the O₂ sensor dry and without hydrocarbons andsulfur compounds present in nebulized medications that could affect itslongevity. O₂ dilution does not change after the cartridge.

Pneumatic connections can be a source of leak which could send corrosiveNO₂ into the device. In some embodiments, the pneumatic connections canbe decreased by using a sensor pack for the acute device that receivesthe water trap/filter assembly into one end and passes gases out theother end. The sensor pack can be installed by sliding in from the frontof the system. In some embodiments, the sample line can include thewater trap.

In some cases, gas sensors have very poor resolution. In someembodiments, another digit of resolution can be obtained by measuringthe percent of time that the final digit flickers high vs. low. Inaddition, NO₂ can be corrosive, thus the sensor line pump can wear ourprematurely from corrosion. In some embodiments, a pump can be includedin the sensor pack so that it is replaced at the same schedule as thegas analysis sensors. In some embodiments, the sensor pack includes alength of Nafion tubing to allow humidity in the atmosphere to enter thegas sample in the event that the gas being sampled is dry. This protectsthe gas analysis sensors from being dried out. In one example, theNafion tubing is 30 cm long.

NO Generation Cartridges

Cartridges are used in an NO generation and delivery system tofacilitate replacement of consumable elements of the system. In oneembodiment, all of the consumable elements are integrated into one NOgeneration cartridge. In other embodiments, referred to as “MultipleCartridge embodiments,” consumable elements such as the scavengermaterial, water trap, inspiratory flow path, inspiratory flow sensor,electrode assembly and spark chamber are independent so that they can bereplaced on independent schedules.

An NO generation cartridge can include a variety of features for theproduction of NO. The electric generation of nitric oxide can consumeelectrode material and scavenger material as well as obstruct filtermaterials. Thus, it is necessary to provide a means of scavenger,electrode and air filter cleaning/refurbishment/replacement.

In some embodiments, a disposable cartridge can include a housing, theincoming plasma air filter, ventilator flow inlet, ventilator flowconduit, ventilator flow outlet, incoming air scavenger material,enclosure air filter, plasma chamber, electrode assembly(s), air pump,ventilator flow measurement, a manual ventilation device flow inlet, amanual ventilation device flow outlet, manual ventilation device circuitflow measurement, manual/backup selector, sample line connection, watertrap, water trap drain, dual NO₂ scavenger paths, a water trap drain,outlet check valves, outlet filters and a memory device. Otherembodiments may include one or more of these elements or a subset ofthese elements.

FIG. 49 illustrates an embodiment of cartridge 740 that includes an airinlet filter 742, an air scavenger 744, vent flow measurements (P1, P2),air inlets 748 into plasma chambers 746, dual scavenger paths 750, amemory device 752, a manual mode selector 754, a water trap 756, and asample line connection 758. A bag outlet 760 is also included and allowsa ventilator bag to be coupled to the cartridge.

The cartridge includes a housing that is configured to encapsulate thevarious features of the cartridge, facilitating the handling and set-upof the system. The cartridge housing is designed with features tofacilitate proper placement of the cartridge into the controller of thesystem, for example, a unique cross-section and/or markings to preventinsertion upside-down or side-ways. In some embodiments, the housing canbe plated or painted with conductive and/or EMI shielding materials toprevent electromagnetic emissions from leaving the system. The housingmay be disposable or reusable. In a reusable design, the cartridgehousing can be opened so that electrodes, filters, and/or scavengermaterial can be replaced prior to the next treatment.

In some embodiments, features presented on the user interface of thesystem align with mechanical connections to the cartridge. For example,the target and measured NO values for the ventilator circuit can belocated above the ventilator connections. The same can be done formanual ventilation device measurements and controls being located in thevicinity of manual ventilation device connections and gas analysismeasurements being near the sample line connection.

In some embodiments, the incoming plasma air filter is hydrophobic toprevent ingress of cleaning solutions including isopropyl alcohol (IPA)into the air flow path. The filter can have a variety of sizes, but inan embodiment, the incoming filter is typically 0.3 μm or less toprevent entry of infectious materials.

In some embodiments, the incoming plasma air scavenger can include sodalime for removal of NO₂, CO₂, and/or other contaminants from the airprior to plasma generation to minimize the potential of unwantedbyproducts. Environmental levels of NO can reach 5-8 ppm, potentiallycreating an offset in NO concentrations in the system output. In orderto provide improved NO output accuracy, the incoming scavenger caninclude a filter, such as a charcoal filter, for removal of NO and otherorganic compounds that could alter plasma generation products.

An enclosure air filter for the controller can be used to remove lintand other large particles from the air used to cool the enclosure. Thisprevents build-up of material on the high voltage surfaces within thecontroller which could decrease effective electrical creepage distances.It also ensures adequate air flow through the controller enclosure forcooling purposes. By including the enclosure air filter within thedisposable cartridge, the number of user steps can be reduced and thepresence of a clean air filter is ensured. In an embodiment, air forplasma generation is sourced from air that has already passed throughthe enclosure air filter such that the incoming plasma air filter isless likely to be clogged with large particles. In a cartridge thatincludes an electrode assembly, it is beneficial to direct the enclosurecooling air over a heat-sink thermally connected to the electrodes.

A ventilator flow conduit, or ventilator tubing, can be connected to thecartridge using various connections, such as a standard 22 mmconnection. Other exemplary connections include but are not limited to a10 mm conical, 15 mm conical, and ¼″ barbs. It will be understood thatthe ventilator tubing can be connected to the controller instead of thecartridge. The ventilator flow conduit can also have various shapes andsizes. In an embodiment, the ventilator flow conduit has a smoothU-shape which allows the conduit to maintain laminar flow of the ventgases and improves the accuracy of ventilator flow measurement. In anembodiment, the conduit can have a T-shape, where the NO is deliveredthrough the stem of the T.

In some embodiments, the ventilator flow conduit can be removable fromthe cartridge to enable cartridge replacement without opening theventilator circuit. The conduit can connect to the cartridge in avariety of locations, including the front, sides, or bottom of thecartridge, but in an exemplary embodiment the conduit can be connectedto the front of the cartridge for ease of use and to decreaseinterference with peripheral equipment.

The plasma chamber houses the one or more electrodes and serves as aconduit for air. The plasma chamber can be formed from a variety ofmaterials, but in an embodiment the plasma chamber is metallic in orderto provide conductive cooling to the electrode assemblies as well aselectromagnetic shielding. The chamber can be made of solid metal,covered with metal, or parts of it may be simply screen to act like aFaraday cage. In some embodiments, the metals block electromagneticradiation, such as ferrous metals or Mu Metal. In the unlikely eventthat flammable materials enter the plasma chamber, the plasma chambercan act as a flame arrestor by providing sufficient cooling throughthermal mass and restricted air flow to choke a flame via a screen ormesh. In some embodiments, the plasma chamber is electrically connectedto a ground electrode and a chassis ground. The plasma chamber can alsoinclude integrated cooling fins for convective cooling. FIG. 74 depictsan embodiment of a Faraday Cage plasma chamber 950 and FIG. 75 depictsan embodiment of a solid metal plasma chamber 952.

The geometry of the plasma chamber can be used to increase theproduction efficiency of NO. For example, increased pressure within theplasma increases the number of N₂ and O₂ molecules that will beaffected, thereby increasing the NO production per joule of energyapplied. In an embodiment, creation of a flow restriction at the exit ofthe plasma chamber can increase the pressure within the plasma chamberwhich can increase NO production efficiency. In an embodiment, pressurewithin the plasma chamber can be increased intermittently with a valveat the exit of the plasma chamber or surges in air flow rate, timed tocoincide with plasma activity in an optimal way.

A cross-sectional area of the gas flow path by the electrodes in theplasma chamber can also affect the NO production. Necking down thecross-sectional area at the plasma so that a greater portion of the gascontacts the plasma can increase NO production efficiency.

When an automotive-style electrode is used, the orientation of theground electrode with respect to the air flow can have an impact on NOproduction and efficiency. In an embodiment, it is desirable to orientthe ground electrode in a repeatable fashion within the spark chamber.This can be done by controlling the orientation of the ground-electrodeto threads during manufacturing of the electrode assembly. In anembodiment, the orientation of the electrode assembly with respect tothe plasma chamber could be controlled with a jam-nut, high frictioninterface (pipe thread for example), or a clamping mechanism.

The electrode assembly can include one or more electrodes. In someembodiments, two independent electrode pairs are present within twoindependent gas flow paths.

In some embodiments, the electrode pairs are mounted within a metallichousing that serves to thermally conduct heat away from the electrodes,and provides electromagnetic shielding. The metallic housing can havecooling fins on its surfaces to increase convective transfer of heat toeither the enclosure cooling air or the plasma air. The metallic housingcan be made from a variety of material. In an embodiment, the metallichousing is made from ferrous materials or Mu metal for electromagneticshielding. In an embodiment, the metallic housing is made from aluminumfor high thermal conductivity and electromagnetic shielding is achievedby another component, such as a coating, paint, or Faraday cagesurrounding the electrode assembly. The coating, paint, or Faraday cagecould be part of the disposable cartridge or part of the controller.

The cartridge can include an air pumping mechanism, such as a diaphragmpump, that is pressed by a solenoid within the controller. Theconfiguration allows the air intended for the patient to stay within thedisposable cartridge.

The cartridge can provide a means for measuring flow rates of thesupplied gases from a ventilator and/or manual ventilation devicecircuit. By means of adaptors, other therapies may be addressed from thesame connections on the cartridge, such as NO delivery to a face mask,nasal cannula, anesthesia circuit, high frequency ventilator, oxygengenerator, and other treatments.

In some embodiments, flow is measured by a sensor, such as a reusabledifferential pressure sensor, within the controller. The cartridgepresents a flow restriction to the subject gas flow and provides apressure tube on either side of the restriction to measure pressuredrop. Pneumatic connections are made between the cartridge and thecontroller to convey the pressure signals to the pressure sensor. Insome embodiments, an electrical pressure sensor is placed within thecartridge and electrical connections are made between the cartridge andthe controller to convey pressure signals to the controllermicroprocessor. This allows for decreased pneumatic connections thatcould leak but introduces additional cost to the disposable cartridge.

The sample line connects to the cartridge with a sample line connection.In an embodiment, the sample line connection can be a detachable,air-tight connection. This connection could be a Luer, a barb, a pushpull connection, or any other connection. In some embodiments, a “pigtail”, or short length of tubing is placed between the cartridge and thesample line connection to move the sample line connection and a sampleline filter away from the face of the cartridge. This can provideadditional working room for making connections to the cartridge withoutincreasing the actual area of the face of the cartridge.

In some embodiments, a HEPA filter is located at the gas outlet of thecartridge (FIG. 89) to serve as a redundant particle filter to capturepotential particulate introduced to the airstream from either the NOgenerator or the inspiratory air source and to protect the cartridgefrom potential contamination from the patient and/or downstreamcomponents. In some embodiments, the HEPA filter is integrated into thecartridge, but in other embodiments, the HEPA Filter is individuallyreplaceable. In some embodiments, the interface between HEPA filter andcartridge is proprietary so that the user cannot connect a ventilatorcircuit without using the HEPA filter.

Multiple Cartridges

In some embodiments, an NO generation system can include more than onecartridge. For example, there can be separate ventilator and scavengercartridges 960, 962, as shown in FIG. 76. Separate cartridges can beused to reduce pneumatic connections within the system, which can assistwith issues involving insertion forces, tolerances required, and flowsensor issues as well as minimizing the potential for pneumatic leaks.The scavenger material is usually the most common component that needsreplacement, so it follows that having a separate scavenger cartridgedecreases the cost of NO therapy by enabling the user to replace thescavenger material more frequently than other components of the system.Exemplary ventilator cartridges 970, 990 are shown in FIG. 77 and FIG.78, and an exemplary scavenger cartridge is shown in FIG. 79. One of themost significant benefits of having a separate ventilator cartridge andscavenger cartridge is that the ventilator circuit is not opened duringscavenger cartridge change because the vent cartridge can remain inplace.

Ventilator Cartridge

A ventilator cartridge can include one or more of the following, asshown in FIG. 77: a ventilator flow inlet 972, ventilator flow outlet974, bag flow inlet 978, bag flow outlet 980, NO flow inlet forventilator 972, NO flow inlet for bag, an NO injector for ventilator976, an NO injector for a bag, means for measuring ventilator flow, andmeans for measuring or supporting the measurement of bag flow. There canbe a variety of rationale for having a ventilator cartridge. In someembodiments, the ventilator cartridge can house flow sensors that canfail from time to time. Flow sensor failure triggers ventilatorcartridge replacement, rather than a more invasive repair. Flow sensorscan be electronic sensors within the ventilator cartridge or pneumatictubes within the ventilator cartridge that connect with differentialpressure sensors within the main device. In some embodiments, one ormore electronic flow sensors with pressure and humidity sensing arelocated within the vent cartridge. In some embodiments, dual flow,pressure and humidity sensors are manufactured into one assembly that ismounted within a ventilator cartridge. In general, electronicconnections to a ventilator cartridge are preferred over pneumaticconnections because they are simpler to test during a system self-test,they are more reliable, and they don't require as much connection forceas pneumatic connections. In some embodiments, more than one size ofventilator cartridge can be provided to the user. This adjusts fordifferent size ventilator connections, different treatment operatingranges (flow rates, pressures, etc.), and/or different internal volumerequirements. In some embodiments, as sensor technology evolves, theventilator cartridge design can be iterated, rather than the entiresystem. In some embodiments, the system only needs one ventilatorcartridge because flow sensors with a wide measurement range can beimplemented (not high flow and low flow). In some embodiments, users andambulances do not have to have both cartridges. In some embodiments,there can be less chance of contamination from a ventilator lineentering the controller. In some embodiments, when a flow sensor withwide flow range is used, user steps to set up the device are reduced ifthe user does not have select a particular size of ventilator cartridge(for example, neonate, pediatric, adult).

A ventilator cartridge is typically used in the dry portion of aventilator circuit (i.e. upstream from the humidifier). In the eventthat a humidifier is used upstream of a vent cartridge, there is apotential for humidity to condense within the ventilator cartridge,potentially decreasing humidity to the patient and damaging electroniccomponents within the NO generation and delivery device or within theventilator cartridge. In some embodiments, a ventilator cartridge isheated to prevent condensation from occurring. In some embodiments, ahumidity sensor within the ventilator cartridge can detect humidifiedgases entering the system and generate an alarm.

In some ventilator cartridge embodiments, there are only barb fittingsfor connecting to a respiratory bag or face mask, as could be applicablein catheter lab applications where the patient is briefly evaluated withNO and is not connected to a ventilator. The cartridge does not have the22 mm vent tube connections. It follows that a controller could have aspecific software mode for catheter lab applications. In one embodiment,the catheter lab mode presents the user with buttons for present NOvalues, 20, 40 and 60 ppm, for example.

The vent cartridge is in series with the patient inspiratory flow. Manyhospitals replace and/or disinfect all tubing between the ventilator andthe patient after a patient is treated. This would include the ventcartridge. In one embodiment, a HEPA filter is placed at the exit of thevent cartridge to prevent contamination of the vent cartridge fromreverse flow within the inspiratory limb. In some embodiments, the HEPAfilter is removable as a separate unit from the vent cartridge. In someembodiments, the HEPA filter connects to the output of a vent cartridgewith a proprietary connection to prevent use of the system without theHEPA filter. In another embodiment, the vent cartridge can bedisinfected via ethylene oxide (EtO), autoclave, alcohol soak, dry heat,wipe down or another means. In order to protect the electronic sensorswithin the vent cartridge, soaking can consist of filling the air flowpath within the vent cartridge with disinfectant, rather than fullysubmerging the vent cartridge. Post-soaking, a drying fixture may beused to hasten the drying process. In one embodiment, the drying fixturedraws air through the vent cartridge under vacuum. Use of vacuum reducesthe pressure within the vent cartridge, increasing the potential ofalcohol droplets to evaporate. Reversing the direction of flow can alsobe used to dislodge droplets. In one embodiment, the vent cartridge isheated to hasten evaporation. In another embodiment, warm air is flowedthrough the vent cartridge during the drying process. A fixture can beused to soak the vent cartridge, dry the vent cartridge, or both stepsin one automated process. In some embodiments, the electronic sensorsare installed in the device and not part of the ventilator cartridge.This allows thorough disinfection or sterilization of the ventilatorcartridge without the risk of damaging electronic sensors.

In the event that a ventilator cartridge is exposed to fluids outside ofthe air flow path, fluids may damage electronic components within thevent cartridge. In some embodiments, a paper tag with ink on it isplaced within the vent cartridge housing. In the event that fluidscontact the ink, the ink spreads leaving a record of the fluid exposure.

In some embodiments, the function of the ventilator cartridge and thescavenger cartridge are combined into a single cartridge. In someembodiments, the scavenger cartridge connects directly to the ventilatorcartridge to reduce pneumatic connections and decrease NO transit timewhile maintaining the ability to replace a scavenger cartridge withoutopening a patient's inspiratory circuit.

Owing to the fact that the rate of NO to NO₂ conversion is faster withhigher levels of NO, it can be advantageous to dilute NO-containing gasinto the inspiratory flow path as soon as possible. In one embodiment,NO-containing gas is added to the inspiratory path prior to scrubbingthe gas for NO₂. In one embodiment, there is a scavenger/HEPA filterinsert at the inspiratory air exit of the vent cartridge. Thescavenger/HEPA filter insert can have a unique connection so that aconventional ventilator tube cannot be connected to prevent errors inassembling the system that could result in the absence of thescavenger/filter insert.

Scavenger Cartridges

The scavenger material in an NO generation and delivery system isconsumed rapidly compared to other components of a system. That beingthe case, the scavenger material can be packaged in a container for easyreplacement by a user. A scavenger cartridge can include of one or moreof the following elements: a housing, one or more product gas inlets,one or more product gas outlets, one or more product gas flow paths, oneor more filters before the scavenger material, one or more filters afterthe scavenger material, and one or more filters mid-path within thescavenger material. In some embodiments, the scavenger cartridge alsocontains filters that clean the incoming air for plasma generationand/or cooling the overall system. In some embodiments, most elements,like the housing, scavenger paths, and connections are reusable and onlythe scavenger material is replaced between uses.

FIG. 79 depicts an embodiment of a scavenger cartridge 1000. Thecartridge 1000 is constructed from an extrusion 1012 and an endcap 1014.The extrusion features eight lumens. Pairs of lumens in connection withthe end cap create “U”-shaped paths filled with scavenger material toscrub product gases for a first ventilation circuit 1002, a secondventilation circuit 1004 and a bag circuit 1006. A seventh lumen 1008 isused to filter and/or scrub incoming air from outside the system. Aneighth lumen 1010 has a grille 1016 on one end and filtration materialwithin. Air from outside the system is drawing through the eighth lumenand used to cool the system enclosure. The end cap is bonded orotherwise affixed to the extrusion with an air-tight seal. Connectionson the other end of the cartridge consist of holes that register withpneumatic fittings within the Controller when the cartridge is inserted.O-rings, lip-seals or a similar approach seal between the reusableportion of the system and the cartridge. In some embodiments, thecartridge housing and pathways are made from polymers, such as ABS,teflon, polypropylene, nylon, and/or polyethylene. Scavenger material isheld within the paths within the cartridge housing with filter plugsthat are pressed into each of the six scavenger paths. The filter plugshave a dual purpose to prevent migration of the scavenger material andfilter out particles that may arise from fracture of the scavengermaterial. In one embodiment, the filter plugs have some elasticity andare inserted in a manner that compresses the scavenger media to preventrelative motion and prevent settling that could open a passage around,rather than through, the scavenger material.

Software Modes

The system can have a variety of software modes. In some embodiments,the system software can include a start-up mode in which the systemboots and performs a self-test. A cartridge check mode can allow thesystem to waits for a cartridge to be inserted and then checks theviability of the cartridge and advance to the next state or mode basedon the type of cartridge. A training mode can be entered when either atraining cartridge is inserted or based on touchscreen inputs. In thetraining mode, the system permits the user to enter all screens anddisplays, however no plasma is generated. A calibration mode is enteredwhen either a calibration cartridge is inserted or based on touchscreeninputs. The system either automatically performs calibration based onplasma generation or instructs the user in how to perform a manualcalibration. A service mode is entered when either a service cartridgeis inserted or based on proprietary touchscreen inputs, for example,from a service technician. The service mode is used to make adjustmentsto the software, hardware and internal settings to the system. A standbymode can be entered when a viable treatment cartridge has been inserted.The system tests the high voltage circuit(s) upon entry into standbymode to confirm that all systems are working properly. A treatment modecan be entered when the user initiates treatment on the user Interface.A sleep can be automatically entered after a set time period of no useractivity in standby mode. The system enters cartridge check mode after asleep mode to ensure that the cartridge is still inserted and has notexpired. For systems that include more than one cartridge, the insertionand/or expiration status for each cartridge is checked during cartridgecheck mode. A patient discharge mode can be entered upon a userindication that the patient treatment is complete. The system instructsthe user on how to close out the patient data file and dispose of thecartridge. FIG. 80 illustrates a flowchart of an embodiment of softwaremodes and the way in which the system moves between modes during systemuse. After start-up 1020, a cartridge check 1022 is performed. There isa treatment mode 1030 for use with a cartridge, as well as standby andsleep modes 1032, 1034. There are also training, calibration, andservice modes 1024, 1026, 1028. FIG. 81 illustrates a flowchart ofanother embodiment of software modes and the way in which the systemmoves between modes during system use. After start-up 1040, a cartridgecheck 1042 is performed. There is a treatment mode 1050 for use with acartridge, as well as standby, idle, patient discharge, and sleep modes1056, 1048, 1054, 1058. There are also training, calibration, andservice modes 1044, 1050, 1046.

In some embodiments, manual mode is entered by a user pressing a manualON button or the detection of the position of a manual selector in thecartridge with a sensor, for example an optical sensor or a contactsensor. Manual mode can be selected from the menus of the userinterface, or manual On/Off can be controlled by voice-activation todecrease the amount of contact the user makes with the NO generationsystem. Once the system enters manual mode, the controller enables amanual ventilation device circuit and redirects the ventilator flowtowards the manual ventilation device.

The presently disclosed embodiments can flow either air or air with NO.Thus, when manual ventilation treatment paused, the system can continueflowing air through the system to purge the system of NO prior tostopping the air pump. This eliminates the need for the user to purgethe system prior to manual ventilation, saving time and reducingtreatment complexity.

In some embodiments, the system can provide continuous NO delivery tothe patient in the event of any single fault. In the event of an NOsensor failure, the system can continue treatment by using the NO₂measurement as a surrogate for NO input. If NO₂ is present, the systemcan be certain that NO is still being produced. The system can also logall information, warnings, and alarms that are presented to the userthroughout a treatment. FIG. 82 depicts an embodiment of an alarm logthat can be viewed as a screen on the GUI. The information displayed inthe log can also be included in the data files for a particulartreatment.

Table 2 illustrates an embodiment of a system installation.

TABLE 2 Step Description 1 Remove Controller from Box 2 Remove powercable from bag 3 Insert power cable into back of controller until it“clicks” 4 Plug Controller into a wall outlet 5 Turn on mains powerswitch 6 Wait for system to boot up 7 Press TBD to enter BME mode 8Enter Hospital Name 9 Enter preferred default settings for NO tolerance,alarm level, privacy mode, and security code. 10 Press TBD to save andexit 11 Remove the calibration cartridge from it's pouch 12 Insert thecalibration cartridge into the cartridge slot until it “clicks”. 13 Thesystem will automatically enter calibration mode and confirm NO and NO2calibration 14 Once system completes calibration and makes a “beep”sound, press the cartridge release button to eject the cartridge. 15Store the Cartridge in a cool, dry location. 16 Leave system ON andplugged into AC power for TBD hours until the internal battery is fullycharged. 17 Unplug AC power cable and wrap it around the winding featureon the back of the device.

Table 3 illustrates an embodiment of mounting to a pole or rail.

TABLE 3 Step Description 1 Remove Controller from Box 2 Remove powercable from bag 3 Insert power cable into back of controller until it“clicks” 4 Plug Controller into a wall outlet 5 Turn on mains powerswitch 6 Wait for system to boot up 7 Press TBD to enter BME mode 8Enter Hospital Name 9 Enter preferred default settings for NO tolerance,alarm level, privacy mode, and security code. 10 Press TBD to save andexit 11 Remove the calibration cartridge from it's pouch 12 Insert thecalibration cartridge into the cartridge slot until it “clicks”. 13 Thesystem will automatically enter calibration mode and confirm NO and NO2calibration 14 Once system completes calibration and makes a “beep”sound, press the cartridge release button to eject the cartridge. 15Store the Cartridge in a cool, dry location. 16 Leave system ON andplugged into AC power for TBD hours until the internal battery is fullycharged. 17 Unplug AC power cable and wrap it around the winding featureon the back of the device.

Table 4 illustrates an embodiment of initiating treatment.

TABLE 4 Use Case 3: Set-up for ventilator use by Nurse/RT InitialCondition: Installed Controller mounted to rail/pole in Sleep mode. StepDescription 1 Press the Power button on the front panel of theController to “wake up” the system. 2 Remove the pouched cartridge fromits box 3 Remove the cartridge from it's pouch by tearing thevacume-sealed pouch 4 Orient the cartridge with the ventilation tubestowards you and the air filter on your left. 5 Insert the cartridge intothe Controller cartridge slot. 6 At the end of the cartridge travel intothe slot, grasp the sides of the Controller enclosure and press thecartridge in with both thumbs until there is an audible “click” 7Confirm that the Controller recognizes the cartridge. 8 Using theprovided, short ventilator tube, Connect Ventilator Inspiratory line tothe cartridge inlet (left) 9 Connect the ventilator expiratoryline/humdifier line to the cartridge exit (right) 10 Connect theInspiratory Line T-fitting to the patient inspritory line beside thePatient Y. 11 Connect the filter of the sample line to the cartridge andtighten by hand. 12 If the default setting of 20 ppm is not desired,press the up/down buttons to alter the prescribed NO level. 13 Press theCase Data key to enter patient information. NOTE: This step can be doneafter treatment begins if there is insufficient time. 14 Press the Startbutton to begin delivering NO

Table 5 illustrates an embodiment of adjusting settings mid-treatment.

TABLE 5 Use Case 3: Adjust settings mid-treatment by Nurse/RT InitialCondition: System is actively treating a patient Step Description 1NOTE: Treatment does not need to be stopped in order to alter treatmentsettings. 2 Press the up/down buttons corresponding the change intreatment desired. NOTE: The preset button can also be pressed forlarger changes.

Table 6 illustrates an embodiment of a system tear down, post treatment.

TABLE 6 Use Case 4: Tear down system - post treatment by Nurse/RTInitial Condition: System is actively treating a patient StepDescription 1 Press “Stop Treatment” on the User Interface 2 Disconnectthe sample line from the T-fitting in patient inspiratory line. 3 Plugthe sample line connection for continued use. NOTE: T-fitting isdiscarded with the patient Y and inspiratory line. 4 Disconnectventilator tubing at the ventilator 5 Disconnect ventilator tubing atthe cartridge exit. 6 Press the Cartridge eject button 7 Discard thecartridge (TBD) 8 The controller will automativally go to sleep after 15minutes with no input.

Table 7 illustrates an embodiment of a system calibration with acalibration cartridge.

TABLE 7 Use Case 5: Calibrate system by Biomedical Engineer InitialCondition: System is ON and in Idle mode. Step Description 1 Insertcalibration cartridge into the Controller 2 Wait for the Controller toperform the automated sensor calibration process for NO and NO2. 3 Whenthe calibration process is complete, the Controller will emit a soundand show the calibration status on the User Interface. 4 Press thecartridge eject button to remove the calibration cartridge.

Table 8 illustrates an embodiment of reviewing historical data.

TABLE 8 Use Case 6: Review of Historical Data by Nurse/RT InitialCondition: System is in either Idle mode or actively treating a patient.Step Description 1 Press the Trend button on the GUI. 2 Press theX-adjust button to change the time range, as needed. 3 Press the Donebutton to return to the main screen.

Table 9 illustrates and embodiment of responding to an alarm condition.

TABLE 9 Use Case 7: Respond to alarm condition of low NO InitialCondition: System has detected an alarm condition but has not stoppedtreating the patient. Step Description 1 Press the “Silence Alarm”button. NOTE: Alarms are silenced for 2 minutes. 2 Read the alarmmessage on the User Interface. 3 Follow the device instructions toresolve the alarm condition. 4 NOTE: The system continues to deliver NOduring most alarm conditions.

Table 10 illustrates an embodiment of a use case of patient transport.

TABLE 10 Use Case 8: Patient Transport Initial Condition: System ismounted to a ventilator and treating a patient that is about to betransported Step Description 1 Unplug the AC Power cord 2 Wrap the ACPower cord around the wrapping feature son the Controller enclosure 3Prepare ventilator and other peripheral equipment for transport. 4Transport patient. NOTE: During long transports, use Auxiliary powerinputs when available to preserve battery charge. 5 Upon arrival at thenew location, plug the AC power cord into a wall outlet.

Table 11 illustrates an embodiment of a use case of controller cleaning.

TABLE 11 Use Case 9: Controller Cleaning Initial Condition: Controllerplugged into AC Power and Idle. Step Description 1 NOTE: Do not cleanthe Controller while it is being used to treat a patient. 2 Unplug theController from AC Power 3 Using a damp cloth, wipe down the externalsurface of the Controller. NOTE: Do not spray fluids into the controllerenclosure. NOTE: Do not clean the inside of the cartridge slot. 4 Plugin AC Power.

Table 12 illustrates an embodiment of a use case for initiating manualmode.

TABLE 12 Use Case 10: Initiate Manual/Bag Mode Initial Condition: Systemactively treating a patient in Vent mode. ASSUMPTION: System has Bag airinlet and Bag air outlet and measures flow. Step Description 1 Connectsource of bag air to cartridge bag inlet 2 Connect bag to cartridge bagoutlet 3 Turn Bag selection knob on cartridge to “Bag” mode. 4 Press“Bag” on the touch screen to initiate flow of NO. 5 NOTE: The defaultbag NO concentration is 20 ppm. This level can be adjusted on thesettings page. 6 NOTE: The System will continue delivering NO to thevent circuit until no flow is detected in the vent circuit.

Table 13 illustrates an embodiment of a use case for stopping manualmode.

TABLE 13 Use Case 11: Stop Manual Mode Initial Condition: Systemactively generating NO on the Bag Circuit. ASSUMPTION: System has Bagair inlet and Bag air outlet and measures flow. Step Description 1 Pressthe “Bag” button on the screen to disable Bag mode. 2 Disconnect the bagfrom the cartridge 3 Disconnect the air source from the cartridge. 4Turn the Bag selection knob to the “Vent” setting.

The system can convey alarm status in 360 degrees around a room. Thisfacilitates evaluating treatment status from a distance, sparing theuser from walking up to the device. In an embodiment, this involvesilluminating the handle with a light bar that can change colorsdepending on treatment status, such as green for OK, yellow for warningand red for error.

FIG. 50 and FIG. 83 depict embodiments of the NO generation system withalarm status indicators. In an embodiment, the alarm status indicatorcan be in the form of a light pump of other illumination element in ahandle of the device to display system status. The light bar in can bepositioned in the docking station and/or around the user display on thegenerator. Various colors of light can be used to indicate the status ofthe system. For example, a blue color can indicate that there are noalarms, and a blinking blue light can indicate that battery charging inprocess. A blinking yellow light (sometimes accompanied by a periodicaudible beep) can indicate a warning situation, such as a low battery ora cartridge near end of life. A red blinking light (sometimesaccompanied by continuous audible sound) indicates that a serious alarmstate exists, such as cessation of NO delivery. It will be understoodthat an audible alarm can accompany any of the visual alarm states, andor that an audible alarm can be used without any visual alarm status. Itwill also be understood that any color scheme of light or pattern oflight flashes can be used to indicate the various states of the device.

Cartridge Design

As explained above, the cartridge can include scavenger material. Insome embodiments, the scavenger flow-paths can be constructed fromTeflon tubing, filled with scavenger material and filters pressed intothe ends. Humidity increases the efficacy of a soda lime scavenger byroughly 20%. In some embodiments, the air is bubbled through waterpre-spark or post-spark and pre-scavenger to add humidity. Using thisapproach, humidity can increase by 40% relative humidity, resulting in aroughly 20% improvement in NO₂ absorption. It should be noted that insome dry environments, humidity may need to be added to the incoming airto have sufficient NO₂ scavenging for patient safety. In addition,electrochemical gas analysis sensors can be adversely affected by dryair, thus humidity may need to be added for them to function accurately.

Flow Measurement

Regarding the measurement of patient inspiratory flow, the range of flowrates within the ventilator circuit can vary significantly. This rangecan exceed the range of an individual flow sensor. In some embodiments,a flow restriction can be used within the flow path with two or moredifferential pressure sensors in a parallel configuration measuring thesame differential pressure. The pressure sensors can have differentranges for high and low ventilator flow rates. In some embodiments, anelastomeric region can be present in the vent flow path that can bedeformed from the outside to create an additional flow restriction whenflows are low. This can increase the pressure drop so that pressuresensors can accurately measure the flow. In some embodiments, a cylinderor other obstruction to the vent flow can be introduced to increase thepressure drop during low flow. For example, a cylinder translated by asolenoid can be used.

System Configuration

FIG. 84 is an exemplary embodiment of a system for generating NO. Inorder to have fully redundant operation in the event of a controlsoftware fault, the HV Circuits 1070, 1072 have additional functionalitythat allows for vent flow measurement and spark chamber pressuremeasurement. A power circuit as shown in FIG. 84 can be separated from acontrol board so that it can be double-sided, making it smaller andeasier to locate within the controller enclosure. The system can includea nurse call feature 1060 in communication with a monitor and controlboard 1061, a sensor bank 1062 with a pump that receives sample gas froma sample line 1063, and an added external DC power from anambulance/automobile/aircraft. The system can utilize redundant plasmaassemblies and separate scavenger and ventilator cartridges 1066, 1064that connect to the manifold 1068. A watchdog component 1070 monitorsthe control software and high voltage circuit software activity. In theevent that software fails, the watchdog circuit can reset the software.After multiple attempts, the watchdog circuit can initiate an alarm(audible and visual) to notify a user that the system has beencompromised. The watchdog circuit and its alarm are powered byindependent battery so ensure operation in the event of power failure aswell.

Electromagnetic interference (EMI) can introduce digital communicationerrors and erroneous sensor readings. In one embodiment, the systemtimes sensor readings to occur when there is no plasma activity. In someembodiments, the system times digital communications within the systemto occur when there is no plasma activity.

Given that the system can continue NO delivery in the event of a userinterface failure or control software failure, it is important to notifya user that NO is still being delivered even though the display may befrozen or blank. In some embodiments, a separate indicator can beprovided that signifies NO delivery, such as a blue LED. In someembodiments, separate blue LEDs are used to represent NO generation ineach of two plasma chambers. In cases where the watchdog alarm istriggered, the visual alarm can be flashing red (indicating alarm) andblue (indicating NO is being delivered). Furthermore, voice alarms cannotify a user that NO is being delivered by playing a voice recording inthe appropriate language.

The cartridge or cartridges used with the system can have variousconfigurations and combination of components. In some embodiments, acartridge with only scavenger and water trap can be used. Vent flow cango through the controller only, which enables better flow measurement, acheaper disposable, and fewer gas connections. In some embodiments, thescavenger and water trap can be separated. The water trap can be part ofthe sample line and connect directly to the sensor pack. This candecrease the number of pneumatic connections in the system withoutadding any user steps to set up the system.

It is possible that the pressure in the ventilator circuit can increasewhen air is pushed to the patient by the ventilator. This increasedpressure can stall flow through an NO delivery device. In someembodiments, a venturi can suck NO into the vent flow like a carburetorsucks gas in. Thus, increased vent flow increases NO flow. In someembodiments, a flow restriction can be included after the plasma to keepthe NO-containing gas pressure high in the spark chamber and increase NOoutput. This flow restriction can be useful for altitude compensation.In some embodiments, a flow restriction can be included at the end ofthe scavenger so that NO-containing gas is at higher pressure than theinspiratory limb of the ventilation circuit and can flow into the ventflow at all times, including when the vent flow is at high pressure. Insome embodiments, a feedback control on the pump can be used to maintainconstant pressure in a spark chamber. This can account for variance inambient pressure and pre-scavenger resistance. Spark chamber pressurecan also be used as an input into the NO generation control algorithm.In some embodiments, a variable orifice can be included downstream ofthe plasma chamber to allow pressure to build up, and the orifice canopen to increase NO flow during an inspiratory pulse. In someembodiments, the system can include two pistons/chambers. One chambercan fill during patient inhalation and deliver gas to the bias flowwithin the ventilator circuit during patient exhalation. The otherchamber can fill during patient exhalation and deliver gas to theventilator circuit during patient inhalation. In some embodiments, asingle piston with chambers on either side can be used. As the pistonmoves one direction, it delivers air for bias flow. As the piston movesin the other direction, it delivers air for inspiratory flow. In someembodiments, the piston can deliver both bias flow and inspiratory pulsegas in one direction before reversing direction and delivering bias flowand inspiratory pulse gas.

FIG. 85 illustrates an embodiment of a piston-pump configuration, andFIG. 86 illustrates a graph demonstrating synchronization of inspiratoryevents in the ventilator flow and injection flow using the piston-pumpconfiguration of FIG. 85. Air is drawn into the system through a filter1080 and flows to either a piston cylinder 1084 or a pump 1082. FS1 1091measures the flow within the patient inspiratory limb to provide timinginformation to a dose controller 1086. FS2 1092 measures the flow rateout of the system for closed-loop feedback of the NO-containing gasflow. FD2 can be located anywhere along the NO flow path between theintersection of pump and piston-cylinder flow and the intersectionbetween NO generation device flow and patient inspiratory flow. The pumpcan be used to create a constant flow rate to match the bias flow of theventilator 1088, and the piston 1084 can be used to create a bolus tomatch the inspiration bolus of the ventilator 1088. The function of thepiston is timed with the ventilator. While the piston shown in FIG. 85is positioned to adjust the flow before the spark that generates the NO,the piston can also be positioned in other locations in the system,including after the generation of NO. FIG. 87 illustrates a graph of NOconcentration versus time during the experiment depicted in FIG. 86,showing that constant NO concentrations can be delivered to the patient.

FIG. 88 illustrates an embodiment of a reservoir configuration and FIG.89 illustrates a graph comparing ventilator flow 1120, plasma air flow1122, and NO levels 1124. This configuration involves two redundant flowpaths 1100, 1102. Each flow path includes a pump that fills a reservoir(RES) 1104, 1106 and first pressure sensors P1, P3 to sense pressurewithin the reservoir. A feedback loop exists so that the pumps arecontrolled based on the pressure of their respective reservoir. Avariable flow restrictor FR1, FR2 are used to adjust the flow rate ofthe gas from the reservoirs through the spark chamber based on flowmeasured in the ventilator inspiratory limb flow sensor 1108. Flowsensors FS1, FS2 are used for feedback to the control system foradjusting the variable flow restrictor setting. Flow rates can vary, forexample, from 0 to 4 lpm. Additional pressure sensors (P2 & P4) measurethe pressure within the plasma chamber 1110, 1112 as an input into theoverall NO generation control algorithm. Air flows from the plasmachamber located in the manifold, a reusable portion of the controller,to the scavenger cartridge where it flows through afilter/scavenger/filter (FSF) as shown. Check-valves in each path ensurethat pressure transients in the ventilator inspiratory limb do notreverse the flow in the NO generation paths.

FIG. 90 depicts an embodiment of a similar system to the embodimentshown in FIG. 88 with the following exceptions. Flow directors are shownin flow path A. The first (upper) flow director can direct flow toeither the gas analysis sensors for calibration purposes or to the ventflow. The second (lower) flow director can direct flow to either thevent flow or to the bag flow. Functions within the scavenger cartridgeare located within the green rectangles shown. Blue lines representdisposable paths and features while red indicates reusable componentswithin the controller. Ventilator and bag flow are shown as verticalblue lines on the right side of the illustration. In some embodiments,flow is measured by two pressure sensors within the controller, shown inred. The two pressure sensors may be identical for redundancy, or theymay have different ranges of accuracy to enable the system to measure awider range of ventilatory flows. Purple-shaded zones identifycomponents connected to the controller manifold. Yellow-shaded zonesidentify components within the vent cartridge. Green-shaded zonesidentify components within the scavenger cartridge. The sensor pack isshaded blue.

FIG. 91 illustrates an embodiment of a system with dual flow paths 1130,1132. Under normal, ventilator treatment, one channel labeled “B” istuned to deliver a constant amount of NO based on the ventilator biasflow. The other channel labeled “I” provides pulsatile flow to deliverNO in proportion the inspiratory bolus from the ventilator. Valves 1134,1136 in each path can close off air flow when a flow path is not active.Flow through each path can be varied by pump rate and the amount of timeeach valve is open. Plasma activity in a flow channel is typicallyconstant when air is flowing so that the only variable in NO productioncontrol is air flow. Check valves 1138, 1140 at the end of each flowpath ensure that ventilator flow does not flow back into the systemduring moments of high inspiratory pressure. A graph 1142 illustrateshow a valve can be open 100% of the time during inspiratory flow andintermittently during bias flow so that a single flow path can provideall the NO for a treatment. In another mode of operation, one flow pathcould be used for bias flow and the other flow path used for inspiratoryflow to even the wear on each flow path. Pulses 0.4 seconds in lengthwith a duty cycle of 50% are not detectable at the patient Y due tomixing that occurs along the length of the inspiratory limb as the NOflows through the patient humidifier and vent tubing.

FIG. 92 illustrates a sample flow path with a single pump 1150 providingair flow. The flow path bifurcates with a single fixed orifice used toelevate pressure within the system and provide NO during bias flow. Avariable orifice 1152 is tuned to provide the desired flow rate duringinspiratory pulses within the ventilator circuit. A valve downstream ofthe variable orifice controls when flow travels through the inspiratoryflow path. The variable orifice 1152 can close down to zero flow or alow flow rate. At the bottom of the illustration is the plasma chamber.In some embodiments, the valve 1154 enables the system to quickly turnON and OFF the inspiratory flow. In some embodiments, the valve is notrequired owing to a very vast acting variable orifice. The entire flowpath shown in FIG. 92 can be duplicated within a device for redundancyor for dosing a ventilator circuit, calibration, and/or a bag circuitsimultaneously.

FIG. 93 illustrates an embodiment of a flow path consisting of a pump1160 and a flow director 1162. The flow director 1162 switches flowbetween an orifice 1164 set for bias flow and a variable orifice 1166set for the sum of inspiratory flow and bias flow. The variable orificecan be adjusted mid-inspiration to further tune the air flow, as needed.The plasma chamber 1168 is shown at the bottom of the image.

FIG. 94 illustrates an embodiment of a system that varies air flowthrough a plasma chamber 1172 to provide an accurate dose of NO to apatient. A target dose is selected by a user or physician. A patientparameter can be sensed and used by a dose controller 1170 to indicatethe timing and/or magnitude of a patient inspiration. Examples ofpatient parameters include but are not limited to patient inspirationdetection, ventilator circuit pressure, ventilator circuit flow, nasalcannula pressure, thoracic wall strain, diaphragm EMG, oxygen generatorpressure, and oxygen generator flow. Air or another N₂ and O₂-containinggas is sourced from a pump or compressed gas source. The dose controller1170 can control the flow of the pressurized gas. This can be done in avariety of ways, including by varying the size of an orifice or the dutycycle of a valve.

The patient dose can be defined in many ways. The most conventionalmeans is to provide the patient with a particular concentration of NO atall times. More sophisticated approaches calculate a target number of NOmolecules to be delivered per unit time based on the size of thepatient's lungs (typically ideal body weight is used as a surrogate).With this approach, the system generates and delivers only enough NO tokeep the lung lining appropriately dosed. NO delivery may beintermittent to achieve the target number of molecules per minute. Thesystem is programmed with the ideal number of molecules per minute basedon the patient's ideal body weight. The system can vary the NOconcentration per breath from zero to a maximum value (typically 80 ppm)with each breath so that the moving average of molecules delivered perunit time is accurate. This approach provides the lining of the lung anappropriate amount of NO molecules, despite variation in breathing thatcan occur based on activity level and respiratory rate.

Changes in dose can be controlled by varying plasma activity and/or airflow rate. In one embodiment, these two parameters are varied to achievea constant concentration of NO-containing gas before dilution into apatient airstream. In another embodiment, air flow is varied inproportion to patient inspiratory activity (e.g. inspiratory air flowrate, ventilator flow signals, breath detection) while plasma activity(pulse width or pulse frequency or pulse power) is varied to generatethe target NO concentration in the NO-containing gas.

In some embodiments, the source of the pressurized gas shown in FIG. 94is controlled by the dose controller is controlled in addition to theflow controller. In another embodiment, the dose controller onlycontrols the source of the pressurized gas.

FIG. 95 illustrates an embodiment of a dose controller 1180 that variestreatment based on a patient parameter and treatment setting. In someembodiments, a pressurized air source 1182 is connected to two or moreflow controllers 1184, 1186. The dose controller 1180 can control thestatus of each flow controller, i.e. the orifice size and flow rate(from 0 to wide open). One pressurized air source servicing a pluralityof flow controls permits the use of slow dynamic response flow controlelements because each flow controller remains at a relatively constantset point (the dynamic response is less important). In this case, thesingle pressurized air source must still address rapidly varying airdemand.

FIG. 96 illustrates an embodiment of a dose controller 1190 that variestreatment based on a patient parameter and treatment setting. In someembodiments, more than one pressurized air source 1192, 1194 is used tosend air through more than one flow path. Examples of pressurized airsources include but are not limited to compressed gas reservoirs, airpumps, and house air services. Use of a plurality of pressurized airsources (pump, etc.) servicing a plurality of flow controllers 1196,1198 permits each air source and flow controller to operate atrelatively constant operating levels. Thus, no pressurized air source isrequired to address rapidly-changing demand.

FIG. 97 illustrates an embodiment similar to FIG. 96 where the dosecontroller 1200 has additional control over the pressure source. Eachpressurized air source can be tuned to the flow required for its flowpath. For example, the pressure in a gas reservoir can be adjusted witha regulator, or a pump speed could be adjusted.

FIG. 98 illustrates an embodiment of a system for generating NO. Thesystem can include a touchscreen interface 1210, a main circuit andpower board 1212, a high voltage & treatment control circuit board 1214,a water trap 1216 from a sample line, a scavenger cartridge 1218, amanifold 1220, an electrode assembly 1222, a power entry module 1224,flow directors 1226, an air pump 1228, an AC/DC power transformer 1230,and batteries 1232.

The system can use a flow-director to redirect flow from one of theplasma chambers to the gas analysis sensors for calibration. The systemcan use a flow-director to redirect flow from one of the plasma chambersto the bag flow circuit for NO delivery during manual ventilation.

The system can use a vent cartridge that includes a vent flow path and abag flow path. Vent flow can be measured as it flows through the ventcartridge. This can be done by a sensor within the vent cartridge or byone or more pressure sensors within the controller that arepneumatically connected to the vent flow with an appropriate flowrestriction between locations sensed. For vent cartridges that containsensors, calibration information for the sensors can be written to amemory device within the vent cartridge. Additional data written to thevent cartridge can include any of the following: serial number, lotnumber, whether or not it has been installed, treatment data, settingslog, alarms log, and user-entered notations. Given that the ventcartridge is integral to the inspiratory flow path, it is desirable totransfer a vent cartridge from on controller to another in the event ofa system malfunction or transfer a patient from one facility to another.By writing the treatment history and settings to the vent cartridge, thetreatment can continue seamlessly in the next controller. The system canalso function with two or more types of vent cartridges. Vent cartridgescan vary by tubing connections, tubing diameter, and/or flow restriction(for flow measurement). In some embodiments, the vent cartridge caninclude the electrode assembly. The low flow vent cartridge can have asmall electrode gap for lower NO production. The high flow ventcartridge can have a larger electrode gap (for example, 2-3 mm) forhigher NO production.

An NO generation system needs to quickly calculate the dose for NOdelivery based on measured flow levels, generate that dose and deliverit to the main airstream. Some aspects that contribute to a system beingable to respond quickly are using look up tables, fast processors, oneor more quick acting proportional valves, low flow restrictionscavengers, short pneumatic pathways and a high pressure gas source(reservoir, pump). Despite these efforts to respond quickly, a systemcan still lag sufficiently that a specific of bolus of NO may beintroduced to the gas flow behind the bolus of gas it was meant for. Byintroducing the NO-containing flow in the center of the mainstream gasflow and at a higher velocity than the mainstream gas flow, it ispossible for the NO-containing bolus of flow to actually catch up withthe gas bolus that it was intended for. The velocity of the exiting NOflow is varied by the orifice size in the injector, gas pressure and gasflow rate.

Another approach to dosing a bolus of patient gas sufficiently is toaccount for system lags by overshooting on the dose to deliver. Forexample, if a bolus of mainstream flow is detected that requires 20 ppmNO, the system may set the plasma and/or flow parameters to generate 40ppm for a brief amount of time so that the system responds more quicklyto the demand. As the actual dose delivered crosses the 20 ppmthreshold, the system could change its settings to deliver 20 ppm.

In some embodiments, the system can include three electrode assembliesand NO paths and three scavengers, with two for vent NO delivery and onefor bag NO delivery.

Sample sensors can receive flow from either the patient inspiratorylimb, a calibration gas cylinder connected to the sample lineconnection, or the NO generation device for calibration, and the sourceof NO can be selected. In some embodiments, as shown in FIG. 99, a pump1240 within the sensor pack 1242 can be positioned between the sampleline connection and intersection between sensor path andself-calibration gas source 1244. A reusable flow sensor (FS) 1246 isshown to the right of the sensor pack and is part of the overall NOgeneration device. Gases from the sensor pack 1242 flow through amanifold, to the flow sensor and on to an exit port. In anotherembodiment (not shown), a ON/OFF valve is in the location of the pump inFIG. 65 to block flow from the sample line connection so that flowpumped from the controller can pass through the sample sensors. In someembodiments, as shown in FIG. 73, a flow selector can be within thesensor pack that can choose between a sample line and a self-calibrationgas source path.

Safety

Various safety features can be incorporated into the system to solve avariety of issues. For example, the system can have a scavenger at thepatient Y before sample collection that is configured to absorb any NO₂formed due to long inspiratory circuits or high O₂ levels.

NO delivery to a patient can be done in emergency situations, thus timeto NO delivery can be important. If the device requires a lot of time toprime the pneumatic pathway, this could present a delay in patienttreatment. In some embodiments, the system can have a mode to rapidlyprime the cartridge with NO before connecting it to the vent circuitafter cartridge replacement. In some embodiments, the system primesitself by pumping air at a rapid rate through a plasma in the plasmachamber and the scavenger cartridge before directing the flow to the gasanalysis sensors. This priming can take place for a set amount of timeor until NO is detected at the NO sensor. Then, the system can decreasethe pump speed and direct the flow to the vent cartridge for treatment.This can result in a decrease in the amount of time required to primethe system, thereby decreasing the time that the patient is without NO.

It can be important to restrict operation of a hospital device to peoplethat are authorized and trained to operate the equipment. In someembodiments, an RFID label can be associated or attached to an ID cardof user, with the RFID having a unique number within it that is used toidentify the user. In some embodiments, the same RFID reader within thecontroller can be used to identify the disposable components (forexample vent cartridge, scavenger cartridge, and/or sample line) as theuser ID badge. An RFID reader can be positioned in various locations,but in some embodiments an RFID reader can be on the side of thecontroller so that it can read the RFID tags on the cartridges on oneside and the hospital ID on the external-facing side of the reader. AnRFID tag can also be attached to the controller within the field of viewof the RFID reader. This enables the software to test the RFID readerbecause there should always be an RFID tag in the field of view. It alsoenables the software to know which controller is performing thetreatment. Other information could be placed in the controller RFID tag,such as the controller serial number, last service date, date ofmanufacture, error codes, run time of the system, run time of variouscomponents, service logs, and other information that could assist withpatient treatment, diagnostics, and/or service and repair.

Sometimes, clinical personnel have to write by hand the NO drugindication into their records. In order to improve accuracy and safety,in some embodiments the system can show a bar code on the user interfacethat can be scanned into the hospital system.

In some embodiments, the system can receive compressed air from anexternal source, such as the hospital air supply or a compressed gascylinder. This approach can also serve as a back-up air supply in theevent that an internal pump/blower fails.

Infection Control

When used with a ventilator circuit, the NO generator is typicallylocated between the ventilator and the humidifier, i.e. the dry portionof the circuit. There is still potential, albeit small, for infectiousmaterials to travel from the patient to the NO generator and contaminatecomponents of the NO generator. This presents a risk ofcross-contamination when the NO generator is used to treat a differentpatient.

In some embodiments, a HEPA filter is located at the outlet of the NOgeneration device. In systems utilizing a vent cartridge, the HEPAfilter would be located on the exit of the vent cartridge. For thepurpose of preventing contamination, the filter must be located inseries between the NO generator and the patient. In some embodiments,the filter is connected to the humidifier and does not directly contactthe NO generator. In addition to preventing transfer of infectiousmaterials from the ventilation circuit to the NO generation device, aHEPA filter between the NO generation device and patient serves tocapture any metallic particles or scavenger material particlesintroduced to the air stream by the NO generator.

Service Life

Each component of an NO generation system has a service life. Theenclosure, for example is designed to last 10 years of more.Alternatively, valves are designed for a certain number of cycles. Inone embodiment, the NO generation system counts the number of cyclesthat a valve has undergone. Based on the acceptable number of cycles,the NO generation system can recommend replacement of the valve prior tothe service life being exceeded. Similar logging can be done for pumprun time, proportional valve cycles, electrical discharge count, andactions that wear components.

When a component is nearing the end of service, the NO generation systemcan use the back-up NO generation system, leaving the worn component asa back-up rather than the primary thereby prolonging the use of thesystem with a functional back-up. In one embodiment, the system uses itsone or more redundant systems evenly throughout the service life so thatcomponents wear at a similar rate across one or more flow paths.

In one embodiment, an accelerometer with in the NO generation system isused to detect vibrations in the system. Vibrations are used asindicators that components are functioning properly. They are alsoindicators that components have worn and/or are not functioningproperly. In one embodiment, the system uses an accelerometer to detectvibrations that are indicative of a worn pump.

In one embodiment, a microphone within the system is used to verify thatvarious components are functioning properly by detecting the sound ofvarious components. Detection of components could be done sequentiallyas each component is powered or actuated during the power-up-self test.

Gas Analysis

In one embodiment, NO and/or NO₂ content within the product gas ismeasured using spectroscopy. In one embodiment, the spectroscopy isbased on infra-red absorption.

System Power-Up Self-Test

In one embodiment, the system directs product gases from the plasmachamber to the gas analysis sensors during power-up self-test to confirmthat the gas sensors are functioning and the NO generation system isfunctioning. In one embodiment, the accuracy of the NO production duringpower-on self-test is accurate enough that gas sensors can becalibrated. In one embodiment, an alarm prompting gas sensor replacementis generated when either NO or NO₂ indicated levels are not consistentwith NO/NO₂ production settings during self-test NO production.

In some embodiments, the system can be configured with pressure sensorsand valves to perform an internal pressure test to sense the pneumaticintegrity of the system. In such a self-test, valves are configured toclose off air flow. The pump pressurizes all or a portion of thepneumatic pathway. In one embodiment, the pump stops and a leak-downtest is conducted by monitoring the drop in pressure within the systemover time. In another embodiment, the pump continues operating and theflow through the system is measured, with flow above a certain thresholdindicating a leak.

Digital Communications

Electrical discharge events and high voltage can emit electromagneticemissions that interfere with electrical signals. This can affect analogsensor readings as well as digital communications. In one embodiment, aNO generation system reads sensors and performs digital communicationsbetween plasma events. In one embodiment, one part of the NO systemgenerates signal that discharge is about to occur. In one embodiment,the high voltage control circuit sends signal that discharge is about tooccur. In one embodiment, the NO generation device uses differentialcommunication signals to provide a level of immunity from EMI.

Power Management

Electrical discharge events can draw high levels of instantaneous power.This can cause current spikes which present challenge to battery powereddevices. In one embodiment, current spikes are addressed by hold-upcapacitors. In another embodiment, current spikes are addressed by apre-regulator. In some embodiments, an intermediate power factorcorrection stage is used to make the NO generation load look to thebatteries like a load that the supply can deliver. In some embodiments,Power Factor Correction (PFC) is used to manage the load on one or morebatteries to an acceptable level.

Alternative Applications

There are a variety of applications for use of an NO generation system,including for use with patients requiring defibrillation to improveoxygenation and likelihood of heart restarting or regaining normalrhythm. In addition, there is an application of NO for patientsexperiencing an asthma attack to improve oxygenation, or for sportsperformance enhancement in various fields, including cycling, football,snow skiing, high elevation compensation, and aviation.

Cloud Connectivity

An NO generation device can benefit from connecting to the internet.Connections may be made by GSM, WiFi, ethernet cable or other means.Once connected the system can exchange information with servers fortechnical assistance, treatment assistance, billing and other dataexchange purposes. The cloud can also be used to transfer treatmentdata, settings, alarm logs, user comments, service logs, scavengercartridge status, and other information from one controller to anothercontroller.

Ambulatory Device

There can also be systems and methods for portable and compact nitricoxide (NO) generation that can be embedded into other therapeuticdevices or used alone. The portable NO generation device allows NO to begenerated and delivered to a patient in any location or setting as thedevice is small enough to be mobile and used anywhere, including in ahome of a patient or during travel. The size and portability of theambulatory NO generation system allows a patient use the systemon-the-go outside a hospital and to have the benefit of NO deliverythrough a respiratory gas delivery device without having to be in ahospital, clinic or other medical setting. In some embodiments, anambulatory NO generation system can be comprised of a controller anddisposable cartridge. The cartridge can contain filters and scavengersfor preparing the gas used for NO generation and for scrubbing outputgases prior to patient inhalation. The system can utilize an oxygenconcentrator to increase nitric oxide production and compliment oxygengenerator activity as an independent device.

The generated NO can be delivered to the patient in a variety of ways.In some embodiments, the NO is delivered through a nasal cannula. Thegases exit an array of holes in the vicinity of the nose of the patientand mix in the space between the cannula and the nose. The cannula caninclude a variety of configurations.

When a patient inspires gas from a nasal cannula, air from theenvironment entrains and is added to the flow, thereby diluting the gasdelivered. In some embodiments, a nasal cannula with unique nose prongsthat have a skirt around them can be used to decrease the dilution ofthe delivered gas. The skirt acts like a check valve, permittingexhalation flow around the prong, but sealing against the nostril wallto prevent entrainment of ambient air. An exemplary nasal cannula 1250having features to prevent dilution of the delivered gas is shown inFIG. 100.

A nasal cannula can also include features to allow for identification ofthe device. In some embodiments, a nasal cannula can include a uniqueidentifier to allow the cannula to be identified. The unique identifiedcan be positioned in various locations, including in a connector of thenasal cannula. The identifier can have various forms, including an RFIDfor wireless, a smart chip for direct electrical connection, a smart barcode to be read optically, or any other mechanism that would allow foridentification. A controller can monitor how long the cannula is in useand can write to a memory device within the cannula to indicate it isused up and needs to be replaced or repaired. This can also prevent theuse of a non-compatible cannula that could result in higher NO₂ levels.Other types of information that can be written to the cannula memorydevice are: part number, lot number, date of manufacture, date ofexpiration, date of first use, new/used status, patient treatmentinformation, a device settings log, a device alarm log, patient logentries, patient parameter data (respiratory rate, heart rate, bodytemperature, SpO₂ level, EtCO₂, activity level).

In some embodiments, a sensor can be placed on the patient to monitorpatient breathing. The sensor can be a microphone, pressure sensor,strain sensor, accelerometer or other type of sensor that detect patientbreathing. In one embodiment, a microphone is placed on the patientneck. In another embodiment, a strain sensor is placed on the skin ofthe patients torso. By detecting patient respiratory activity, such asbreathing rate, breathing depth, breath pulse shape, the NO generationsystem can optimize NO delivery. Patient-mounted sensors may be wired tothe cannula or directly to the NO generator. In other embodiments, thesensors are wireless and communicate via WiFi, Bluetooth, infrared, RFor some other means to the controller.

It is important that an NO generation system have a sufficient amount ofambient air to function properly. As the ambulatory system can belocated or worn by a user in various locations, including being placedin a bag or worn under an article of clothing, it can be possible thatthe device cannot source sufficient air to generate a therapeutic amountof NO. It is possible for the cannula to include features to allow foradditional air to enter the device. In some embodiments, the cannula caninclude one or more extra lumens for sourcing air. The air lumen canhave one or more openings (such as perforations) so that air can enterthe lumen from anywhere along the length of the cannula. Theperforations help ensure that the device can pull air from somewherealong the length of the cannula. An embodiment of a cannula 1260 with anadditional lumen 1262 is shown in FIG. 101.

In some embodiments, a nasal cannula can include one or more small NOtubes that go through each prong so that O₂ does not suppress NO flowdue to its greater flow rate and pressure, as shown in the exemplarycannula 1270 shown in FIG. 102. In some embodiments, a nasal cannula canuse a venturi or jet configuration to draw NO into the O₂ flow.

There are different points along the cannula at which the O₂ and the NOcan be mixed before the gases reach a patient. In some embodiments, itis possible to keep the NO and the O₂ separate as long as possible untilit enters a patient's nose in order to reduce NO₂ formation. The NO₂formation due to high NO concentration is the predominant effect. Insome embodiments, it is possible to mix NO with the O₂ flow as soon aspossible so that transit time to the patient is reduced. Thus, anambulatory device that introduces high concentration NO to the O₂ flowwithin the ambulatory device can offer reduced NO₂ levels at thepatient, as shown in an embodiment of an NO generation device 1280 shownin FIG. 103.

There can be various ways to utilize scavenger material in an ambulatoryNO generation system. In some embodiments, a cannula tube that is thinwalled (as opposed to the thick kink-proof versions) that is filled withscavenger material partially or completely along its length can be used.In some embodiments, a nasal cannula with pre-scavenger in addition toNO scavenger can be used. A controller does not have a cartridge at all,such that the system has one disposable component (a cannula 1290)instead of a cannula and a scavenger cartridge, as shown in FIG. 104. Insome embodiments, a nasal cannula 1290 can include a scavenger near thepoint of inspiration (i.e. close to the nose).

FIG. 105 are multiple views of an embodiment of an ambulatory NOgeneration device 1300. In some embodiments, a top of the device can bereserved for a user interface including but not limited to buttons anddisplay information. Cannula and oxygen connections can be made on anupper edge of a bump on the side of the enclosure. The scavengercartridge 1312 can be located in several locations, including the side(as shown in FIG. 106A) and the bottom (as shown in FIG. 106B) of thedevice 1310. In some embodiments, cannula and O₂ connections are on thetop of the device. The user interface 1314 is on the side, as shown inFIG. 107A. The scavenger 1316 can be on the side, as shown in FIG. 107B,or bottom of the device.

Various methods can be used for respiration detection. In someembodiments, a wire runs up one tube and down the other tube of a nasalcannula. Between the nostrils, there is a piece of Mylar with sputteredaluminum (like a thermistor). Respirations are detected by looking atthe changes in resistance of the thermistor, indicating the warmth ofexhalation of cooling of inhalation. Two wires could run in one tube aswell. In some embodiments, sensing can also be done by stretching thewire to be thinner in the area of temperature sensing. In someembodiments, a barb of a nasal cannula can be metallic and conductive sothat it is part of the thermistor circuit. This works best when there iswire in two lumens and two barb connections to the controller. In someembodiments, a thermocouple under the nose can be provided. In someembodiments, an NO delivery device can include a cannula NO lumen thatbifurcates as it reaches the controller. One lumen connects to thescavenger and the other lumen connects to a blind hole with a pressuresensor for detecting respirations. In some embodiments, an NO deliverydevice is provided where an NO line pressure is sensed within thecontroller near the cannula connection point so that patientrespirations can be sensed via pressure.

Various mechanisms can be used for respiration detection relating toactivity of an O₂ concentrator. In one embodiment, an NO delivery device1320 is provided with a T-fitting that receives O₂ from an O₂ source1322, sends O₂ to patient 1324 (via a cannula), and has a pressuresensor 1326 within the controller at the bottom of a blind hole, asshown in FIG. 108.

In some embodiments, an NO delivery device 1330 is provided with an O₂input connection 1332 and separate O₂ output connection 1334, as shownin FIG. 109. Between the two connections, the system senses pressureand/or flow to detect oxygen concentrator activity. NO and O₂ haveseparate output connections. There can be a single exit point with NOand O₂ combined. In some embodiments, an NO delivery device 1340 isprovided that works in conjunction with an O₂ concentrator that includesa mechanism, such as an RFID reader 1342, to communicate with the NOdelivery device, as shown in FIG. 110.

NO can be delivered to a patient using various techniques relative tothe inspiration of the patient. In some embodiments, a molecular sievecan be used to decrease O₂ content in the gas after sparking. Removal ofO₂ can decrease the rate of conversion to NO₂.

In some embodiments, an NO device that can operate in one or more modes,including a synchronized mode with pulsed NO delivery delivered in syncwith O₂ delivery, an independent mode with pulsed NO delivery deliveredin sync with patient respirations, and a constant mode with constant NOflow rate and concentration. In one embodiment, the NO delivery pulsebegins 50 msec after inspiration detection and lasts 200 msec. Inanother embodiment, the NO delivery pulse lasts the duration ofinspiration.

A patient's respiratory rate may vary with effort. Faster respiratoryrates could lead to excessive NO delivery if the NO generation systemdelivers NO with every breath. It should also be noted that respiratorydepth can vary as well and is generally independent of respiratory rate.For NO treatment to be effective, the concentration of NO in the patientlungs should be at therapeutic levels periodically, if not continuously.In one embodiment, the NO generation system uses respiratory rate, tidalvolume and NO half-life to determine which inspirations to dose. Inanother embodiment, NO is delivered with each breath but pulseparameters are varied based on respiratory rate, tidal volume,entrainment fraction and NO half-life to achieve target NO concentrationwithin the lung. In one embodiment, the NO generation system has amaximum number of breaths that it will dose per unit time. Based on amoving average, if the number of dosed breaths per unit time exceeds athreshold, the device stops NO delivery until the moving average fallsbelow the threshold.

Respiratory events occur quickly, requiring a fast system response todeliver an NO pulse. In some cases, the pulse is delivered 50 msec afterinspiration detection, which is faster than a pump could increase speed(i.e. spin up) and push a bolus of NO-containing gas into the nose. Inone embodiment, an ambulatory device prepares a bolus of NO-containingair in a reservoir during patient expiration. When an inspiration isdetected, air from a compressed source is released, pushing the NO bolusthrough the cannula to the patient. In one embodiment, the stagingreservoir is a lumen within the cannula. In one embodiment, the lumenwithin the cannula is a dedicated NO-delivery lumen. The NO-containinggas can pass through a scrubber before staging in the reservoir, afterthe reservoir, at a location near the patient within the cannula, or notat all if NO₂ levels are sufficiently low.

As the ambulatory device can be placed in various locations, includingon an O₂ generator trolley or a battery charger (for example, positionedat a 45 degree angle for stability and ease of reading a display), or beworn by a patient, for example on a belt, in a bag or worn under a coat,it is possible for the device to overheat. In some embodiments, the airthat is used to generate NO could be run over heat exchangers to coolthe electronics. In one embodiment, the NO generator is located at theair inlet for an O₂ concentrator.

Some users can prefer to connect to a stationary O₂ concentrator when athome and use a line, such as a 50 foot (15 m) line, to receive O₂. Thetransit time of NO in a 50′ line could be long enough that unsafe levelsof NO₂ can form. In some embodiments, a line, such as a 50′ line, can beprovided with proprietary connectors that have an NO₂ scavenger at thepatient end to remove NO₂ close to the patient. For example, aconnection could involve a custom thread, an RFID, a bar code, or otherfeatures.

Various safety features can be included with an ambulatory NO generationdevice. It is possible for users to forget to replace the NO₂ scavengercomponent at appropriate times. In some embodiments, a device can prompta user to replace a scavenger when they remove the device from thecharger in the morning. In some embodiments, an ambulatory device caninclude a built in accelerometer to detect patient activity. In someembodiments, an ambulatory device can include features to detect patientexertion and provide a warning. The warning can be based on variousmeasurements and data, including accelerometer data and/or respiratoryrate.

NO delivery tubing can be kinked during operation, potentially slowingor stopping NO delivery to the patient. In some embodiments, the systemcan use various indicators to detect a kinked line, including but notlimited to NO line pressure, O₂ line pressure, NO pump current, NO lineflow, O₂ line flow, respiration signal fidelity, spark activity(suppressed by high pressure).

It can be possible that patients that breathe through their mouth do notreceive the same dose as when they breathe through their nose whenwearing a nasal cannula. In some embodiments, the system can detectinadequate nasal respiration and/or mouth breathing and can respond byincreasing the NO delivery to accommodate and/or warning a user. If thesystem is able to deliver NO to the patient (pump current is normal, NOflow is normal) but the system is not able to detect respirations at thenose, then the patient is probably breathing through their mouth.

FIGS. 111 and 112 illustrate embodiments of ambulatory NO generationsystems. FIG. 1111 illustrates an embodiment of a portable ambulatory NOgeneration system that includes a delivery device, such as a cannula,for delivering a product gas containing NO to a patient, which includesa filter/scavenger. A controller is configured to control the productionof NO by a plasma chamber using a variety of sensors. The controllerincludes a CPU with LEDs and buttons for communication therewith by auser, a high voltage circuit, a power source, an inductive charger, anda pump controller. FIG. 112 illustrates an embodiment of a portableambulatory NO generation system that includes a delivery device, such asa cannula 32, and a disposable replaceable cartridge 34 that includes ascavenger therein.

FIG. 113 illustrates an embodiment of an NO generation system withredundancy. In the upper left of the figure, sample gases from aninspiratory flow enter a sample line 1350 and travel through a filter1352 and Nafion tubing 1354 to remove humidity from humidified samplesand add humidity to dry samples. The gas then flows through a 1-wayvalve 1356 that prevents contents from the gas sensor circuit fromentering the patient airway. The gas flows through a water trap 1358that removes humidity followed by a hydrophobic filter 1360 and into asample gas pump. Beyond the pump is a critical orifice that governs theflow of gas through the sensors manifold 1361 and diminishes pulsatilityin the flow from the pump. Gases pass through a second Nafion tube 1362that protects the sensors in the case that dry gases as would be usedduring calibration are sent through the sensor pack. Pressure sensorsmonitor the flow and pressure through the sample pack. The gas thenpasses by gas analysis sensors and on past a pressure sensor and one-waycheck valve. Sample gases exit through a T-fitting that has one leg opento atmospheric pressure and provides a barb or small bore connector onthe other leg for connection to hospital vacuum. The open leg toatmospheric prevents vacuum pressure from increasing the flow ratethrough the sensor pack and/or pulling more gases from the patientinspiratory flow than required.

In the middle-top of the figure, two independent flow paths 1366, 1368provide reactant gases to two pumps. The pumps pressurize twoindependent reservoirs 1370, 1372 to a target pressure. In oneembodiment, the target pressure is 2 atm. In each circuit, past thereservoir there is a pressure sensor 1372, 1374 for closed loop-feedbackon reservoir pressure. This sensor could also be before the reservoir orwithin the reservoir so long as it is in fluid communication with thereservoir. A proportional valve 1376, 1378 regulates the exit flow fromeach reservoir. A flow sensor is used for closed-loop feedback to theproportional valve. Gases pass through a plasma chamber 1380, 1382. Theplasma chambers shown include a temperature sensor 1384, 1386 on thechamber wall that can be used for NO algorithm tuning and closed-loopfeedback to the device enclosure fan. Pressure sensors in fluidcommunication with the plasma chambers are used as input into thecontrol algorithm to calculate NO production.

Beyond the plasma chamber and pressure sensors, the flow pathsbifurcate. Shunt paths with a valve provide a means to drive productgases to the gas sensor pack for analysis. Proportional valves after thebifurcation can be used to provide a back pressure within the plasmachamber to compensate for elevation effects and low ambient pressure.The valves use a smaller orifice at higher elevations to increaseback-pressure within the plasma chamber and increase NO production.After the proportional valves, product gas flows through a scavengercartridge containing a filter, scavenger and filter (FSF) for each ofthe two paths. A first path is dedicated for ventilator applicationswhile the second path may scrub gas for a ventilator or a manual bagcircuit, depending on the position of a flow director in the secondpath. A proportional valve located after the FSF in the first (Figureleft) flow path provides a means to sample gases post-FSF as well asevens the flow restriction between the sides.

Product gases flow to a ventilator cartridge 1390 through Channel B forventilator applications of Channel C for manual bagging. Inspiratorygases from a ventilator enter the ventilator cartridge through astandard 22 mm connection prior to flowing through two flow sensors.Each flow sensor reports to a separate NO generator within the devicefor total redundancy. Pressure and/or humidity are also measured at theflow sensors. NO in injected into the patient airstream after the flowmeasurements and prior to gases exiting the vent cartridge through asecond 22 mm fitting. The vent tube fittings can vary with application,from 10 mm for neonate circuits to 15 mm for pediatric applications. Theflow sensors can detect reverse flow so the system can report an alarmif the ventilator circuit tubes have been connected in reverse.

Bag flow comes from an external source which could be an oxygencylinder, blender, wall air, wall O₂, oxygen concentrator or anothersource. The flow connects to the ventilator cartridge with a pneumaticconnection, such as small bore or barb fitting. The flow rate ismeasures by a flow sensor. In the embodiment depicted, flow is measuredby a differential pressure sensor prior to the injection ofNO-containing product gas. The flow then exits the vent cartridgethrough a similar small bore or barb connector and on to the manualrespiration airway.

Current methods of NO therapy monetization on the market involve readingmemory devices on gas cylinders or downloading use data from acontroller to a portable memory device or writing down use data from aninformation screen. A wireless communication device can be incorporatedin an NO generation device for the purposes of billing. This samecapability can be used for remote support, monitoring and diagnosticstoo. The benefits of this concept are several-fold: reducing laborinvolved in obtaining billing information (it's automatically uploadedto the cloud), reducing labor involved in processing billing information(it's automatically calculated on one or more servers), improvingtracking use of devices for service calls, and locating devices within asite.

Electromagnetic Interference (EMI)

Reactant and product gases are routed into and out of the plasmachamber, respectively. The plasma chamber is a source of electromagneticemissions. Plastic tubing carrying the reactant gas present a portal ofelectromagnetic emissions where they connect to the plasma chamber.

In some embodiments, the plastic tubing is covered with anelectrically-conductive mesh along its length from the plasma chamber toat least the first 90 degree bend. In some embodiments, metallic tubingis used to convey reactant and product gases to and from the plasmachamber to absorb EMI. In some embodiments, the manifold is made frommetal or has a metallic coating. The manifold is designed so that thereis no straight path from the exterior of the manifold to the plasmachamber that would provide a conduit for EMI to escape. In someembodiments, one or more grounded flame arrestors in the gas pathwayupstream and/or downstream of the plasma chamber can be used to absorbEMI generated by the electrical discharge.

Modules

Systems and methods of nitric oxide generation and/or delivery for usein various applications can also be in the form of a module for use withvarious types of medical equipment and machines, such as variousventilation and respiratory devices.

In some embodiments, nitric oxide generation and/or gas sensing modulescan integrate with a respiratory device by sharing resources and/orbeing fully embedded therein. The various NO generation modules or NOgeneration devices can control the generation of NO in a variety ofways. In some embodiments, an NO generation device or module can controlNO generation by varying the air flow through a plasma, for example, tomatch a ventilator flow.

In some embodiments, an NO module can be configured to be removablyinserted into module bay of a patient monitor. In some embodiments, anNO module can be physically integrated into a patient monitor. In someembodiment, an NO module can include a spirometry interface to an inlinesensor and NO feeder assembly. The spirometry sensor can be thermistorbased, ultrasound based, hot wire anemometer based, acoustic, microphonebased, delta pressure based, single pressure based or other means. TheNO module can include separate incoming air filter and NO scavengercomponents, or can include a combined air filter and NO scavenger.

A patient monitor can include a dock to receive an NO generation module.The patient monitor can have NO generation capabilities (embedded orremovable) and replaceable air filter and NO₂ scavenger. In someembodiments, a patient monitor with NO generation capability can becoupled to a ventilator and can receive patient spirometry data from theventilator, either using a wired or wireless connection. In someembodiments, a patient ventilator with NO generation capability can becoupled to a patient monitor, receiving patient SpO₂ data from thepatient monitor, using a wired or wireless connection.

Numerous medical procedures involving a variety of equipment can be usedto treat patient with the use of nitric oxide. Various types ofequipment can be used to deliver air to a patient, includingventilators, anaesthesia machines, and C-PAP machines. There are alsovarious types of equipment used to oxygenate patient blood, includingECMO systems that can add nitric oxide to the air/gas mixture. In someembodiments, a nitric oxide generation module can be integrated intovarious types of equipment such that machines/equipment from multiplesuppliers of such equipment can have access to a source of nitric oxide.The NO generation module can leverage various resources within theprimary equipment, including but not limited to electrical power, gassupply or oxygen and/or compressed air, treatment parameters (e.g.,flow, volume, and/or pressure), a user interface, and/or alarm hardware.

An NO generation module coupled to or embedded within a medicalmachine/equipment can decrease user-established pneumatic connections.Pneumatic connections can take time to establish, can leak, andembedding an NO generator in an existing machine/controller caneliminate the need for a user to connect the air-delivery equipment toan external NO generator, thus reducing the number of connections to themachine. Shared hardware between the module and the equipment, such as aventilator, can eliminate some redundancy and can help reduce powerconsumption and improve electrical power efficiency of a giventreatment.

Improved accuracy of treatment parameters can be achieved when using aNO generation module. In some cases, an external NO generator sensesventilator activity with a sensor, such as a flow sensor and/or pressuresensor. An embedded NO generator, such as an NO generation module, canreceive ventilator flow information directly, including flow rate, flowpressure, ventilator mode (pressure control, volume control, highfrequency), and breath timing. This can improve accuracy of treatment byeliminating sensor and algorithm inaccuracies, and reducing lag timerequired to sense, process, and react to sensor readings.

User confusion about oxygen concentration being delivered to the patientcan also be reduced. An external NO generation device can dilute theoxygen concentration in the gases exiting the ventilator, thus the NOgeneration device must have its own O₂ sensor which can have a differentreading than the ventilator. This can introduce user uncertainty. In anintegrated approach using an NO generator module, the ventilator canmeasure O₂ at the ventilator exit, thereby measuring O₂ in a singlelocation that includes the effect of the NO generation module and itspotential O₂ dilution.

The NO generation module can also make use of a display on an associatedmachine or medical device. For example, when coupled to a ventilator, NOgeneration-related information can be displayed on the ventilatordisplay, including but not limited to target NO concentration and actualNO concentration, along with a plurality of ventilation parameters. Thisallows information to be displayed to the user on a single displayrather than having two screens with redundant and/or conflictinginformation. The alarm information can also be consolidated into asingle priority list such that multiple alarms from multiple sources(i.e. the respiratory machine and the NO generation device/module) arenot alerting a user and creating confusion about alarm priorities andimportance.

An NO generation module can be used with a ventilator. In someembodiments, an NO generation module can be removably inserted into adocking location in a ventilator enclosure and can be replaceable by auser when necessary. In some embodiments, an NO generation module can befully or partially enveloped within a ventilator enclosure and can be apermanent feature, as long as there is the capability of user access tothe module to allow for the replacement of certain portions of themodule, such as scavenger material, electrodes, and/or otherconsumables. In both cases, the NO generation module can source powerand input parameters such as target NO settings from the ventilator. Insome embodiments, filtered air for NO generation can be sourced from theventilator or the compressed gas supply of the treatment site. In someembodiments, the NO generation module can use an internal pump to sourceambient air from the room. The NO generation module can send to theventilator the status of NO production, any alarm conditions, and/or NOand NO₂ concentrations (if the module include gas sensors). In bothcases, scavenger material for the removal of NO₂ can be consumed by theNO generation process. Scavenger material can be inserted into themodule or the ventilator in the form of a cartridge that is removableand replaceable. In some embodiments, the ventilator can have ascavenger chamber within the flow path of ventilation gases. The loosescavenger material in the chamber can be replaced periodically, based onthe amount of NO₂ absorbed, treatment time, single patient use, or otherrationale. It will be understood that any of the NO generation modulesdescribed herein can include scavenger material that can be used for theremoval of NO₂ from the gas. The synergy between the ventilator and theNO module can reduce the number of components required to generate NOfor a ventilator circuit. This can save weight and volume of thecombined devices, which can be important for in-hospital orbetween-hospital transport. In some embodiments, some ventilators canhave a humidification feature. NO can be added to the ventilator flowbefore or after humidification.

FIG. 114 illustrates an exemplary embodiment of an NO generation module1400 for use with a ventilator 1402. The NO generation module includesvarious inputs and outputs for gas measurement, which can vary dependingon how various gas levels are measured. As shown in FIG. 114, the NOgeneration module includes an output 1404 of NO/air, and inputs 1406from the ventilator, such as power, a ventilator flow signal and/orsetting, one or more treatment parameters such as a target NOconcentration, and a ventilator pressure signal and/or inspirationtrigger. In some embodiments, the NO generation module can performsample gas measurements, and can include an input 1408 for a sample gas,and an output 1410 to the ventilator in the form of a one or more gasmeasurement readings and/or alarms. The sample gas can be taken fromeither the ventilator or the ventilator circuit. It will be understoodthat the sample gas can be from anywhere in the system before patientinspiration. In some embodiments, the sample gas is taken from theventilator circuit as close as possible to the patient before patientinspiration. In some embodiments, sample gas can be taken at a locationa distance from the patient, and the system can calculate NO₂ levelsbased on factors including but not limited to circuit length, circuitcross section, circuit volume, transit time, NO concentration, O₂concentration, and other parameters that compensate for the distancefrom the patient. In some embodiments, an NO₂ scavenger can be locatedclose to the patient to help ensure that NO₂ remains at an acceptablelevel.

In some embodiments, sample gas measurement can be done within theventilator. In some embodiments, the NO generation module can performsample gas measurements to analyze breathing circuit gases. For example,either the NO generation module can include gas analysis sensors orthere can be a separate gas analysis module that is used in conjunctionwith the NO generation module, such as the modules 1420, 1422 shown inFIG. 115.

In some embodiments, sample gases are drawn from the inspiratory limb,as close as possible before reaching a patient. For example, samplegases can be taken at roughly 6″ upstream from the wye piece of aventilator circuit to avoid interference from exhaled gases. In someembodiments, gases can go through the NO₂ sensor first since NO₂ levelsincrease over time as the NO oxidizes into NO₂ and surplus NO₂ generatedin the sensor pack is not representative of the NO₂ concentrationinspired by the patient. High levels of NO₂ can generate an alarm. Thus,sample gases can go through an NO generation module with gas analysiscapabilities, and the module can pass the sample gases to the ventilatorfrom there for further analysis, if needed. In some embodiments, thegases could be passed by an internal pneumatic connection where themodule connects to the dock or an external connection (i.e. a tuberunning from an NO generation module to a sample gas inlet on theventilator).

Various measurements can be taken by different parts of the system. Insome embodiments, one or more gas sensors can be a separate module inthe ventilator or other device, such as a sensor module, described inmore detail below. NO and NO₂ sensors can be combined with an etCO₂device or other patient monitor, gas monitor, or blood gas monitor. Toprevent spontaneous cessation of NO delivery, the NO module can haveredundant components, such as NO generators, scavengers, electrodeassemblies, control circuits, flow sensors, etc. Flow measurement can bedone by various components. In some embodiments, flow is measured by theventilator, and the measured results can be delivered by a wired(analog, I2C or RS232) or a wireless connection. An NO generation modulecan also measure flow at the ventilator outlet and introduce NO to theventilator flow in the same location. In some embodiments, theventilator and NO generation module can communicate by any acceptableapproach, including but not limited to RS232, I2C, analog signals,optical, wireless such as Bluetooth or other means.

If additional power is needed, an NO generation module can bedouble-width to draw from two power connections from the ventilator(i.e. two module bays). The double-width NO generation module couldinclude the sensor pack, or the sensors can be in a separate module orin the ventilator. Redundant NO generation can draw from the twoindependent power connections for greater redundancy.

An NO generation module can access air and O₂ from a variety of sources.In some embodiments, the NO generation module uses ambient air. In someembodiments, the NO generation module can have its own air pump to moveair through the electrodes and to the ventilator circuit. In someembodiments, the NO generation module can use air from the ventilator.For example, the NO generation module can send NO gas back into theventilator to be added to the vent flow within the ventilator.

FIG. 115 illustrates exemplary embodiment of an NO generation module forgenerating NO to be used by a respiratory device in conjunction with asensor module for measuring information relating to gas concentrationsin the system. In some embodiments, the NO generation module and thesensor module can be coupled to a device, such as a ventilator throughvarious connections and/or ports. In some embodiments, the modules canbe inserted into corresponding ports/bays in the ventilator that includethe proper connections/ports for each module such that the modules areremovably coupled to the ventilator. In some embodiments, the modulescan be embedded into a respiratory device, and be either removable orpermanently fixed therein.

FIG. 116 illustrates an exemplary embodiment of an NO generation module1430. The NO generation module 1430 can include an air inlet 1432 thatis coupled to a variable orifice 1434, or other flow control device, tocontrol the flow of air into the NO generation module. The NO generationmodule can include various sensors, including a flow sensor 1436, atemperature sensor 1438, and a pressure sensor 1440 as shown in FIG.116. The air flows into a plasma chamber 1442 that includes a pluralityof electrodes therein for generating NO. The NO/air exiting the plasmachamber 1442 can pass through a scrubber or a scavenger 1444 to anoutlet. The terms scavenger or scrubber may be used interchangeably. TheNO generation module can include various other inputs and outputs,including but not limited to power 1446, alarms 1448, and treatmentsettings 1450. The NO generation module can also include a high voltagecircuit 1452. The high voltage circuit can be formed from a variety ofcomponents, but in some embodiments the high voltage circuit includes acontroller to receive commands, a resonant circuit and high voltagetransformer. The HV circuit receives commands from the controller andinterprets the commands as plasma parameters and creates pulses ofcurrent that are fed to a resonant circuit and generates AC voltage. TheAC voltage has a frequency that is tuned to the natural resonance of thehigh voltage transformer to maximize electrical efficiency. The AC highvoltage can be applied to the electrodes in the plasma chamber to make adischarge and is continuous until the pulse ends.

In some embodiments, the NO generation module can include a cartridgeconfigured to produce nitric oxide to be delivered to a respiratorydevice or other medical device/equipment. The cartridge can include aninlet for receiving reactant gas, one or more plasma chambers configuredto produce nitric oxide from the reactant gas using one or moreelectrodes, and an outlet for delivering the nitric oxide to therespiratory device. A controller is configured to receive feedback fromthe cartridge to allow the controller to regulate the production ofnitric oxide by the cartridge by adjusting the flow rate of the plasmachamber gas and a duration of plasma activity in the plasma chamber. Thecartridge in the NO generation module can also include one or morescavengers coupled between the one or more plasma chambers and theoutlet, and the one or more scavengers can be configured to remove NO₂and/or ozone from the generated nitric oxide. The cartridge can beremovable and replaceable, or the entire module can be replaced whenrequired.

There are a variety of ways to control NO generation in the NOgeneration module. In some embodiments, air flow rate and spark rate arecontrolled to control the generation of NO in the NO generation module.In some embodiments, air flow rate and spark duty cycle can becontrolled. In some embodiments, air flow rate is varied in response torespiratory flow rate variation. The relationship between air flow rateand respiratory flow rate can be linear, non-linear, logarithmic, orsome other repeatable relation. In some embodiments, plasma pulse ratecan be varied as well to maintain constant NO concentration throughoutthe respiratory cycle. In some embodiments, air pump speed is heldconstant and only plasma control parameters (B=spark groups per second,P=time between discharges, N=number of discharges per group, and H=pulsetime) are varied to produce required NO concentrations based on patientinspiratory flow. In some embodiments, air flow can be generated by anair pump that moves air through the plasma chamber. In some embodiments,a pump can fill a reservoir with pressurized air and a variable flowrestriction can be used to control air flow rate from the reservoirthrough the plasma chamber. In some embodiments that source air from apressurized air source, air flow through the plasma chamber can becontrolled by a variable flow restriction. A flow sensor downstream fromthe variable flow restriction can be used for closed loop feedback tothe variable flow restriction to ensure accurate air flow is achieved.In some embodiments, NO can be generated and accumulated in apressurized reservoir, from which it is dispatched into the ventilatorflow. In some embodiments, air can be sourced from a pressurized airsource, and its pressure and flow are regulated to control flow throughand pressure within the plasma chamber.

Other factors affecting NO generation include but are not limited toflow rate, ambient temperature, plasma chamber pressure (i.e. pressureinside the electrode chamber that sparks to produce the NO), ambientpressure, ambient humidity, and measured NO values in an inspiratoryline. In some embodiments, it is possible that the pressure in theventilator (or other device) circuit can increase when air is pushed tothe patient by the ventilator (or other device). This increased pressurecan stall flow within an NO delivery device. In some embodiments, aventuri can be inserted into a ventilator circuit. A high flow rate inthe venturi can lead to low pressure in a venturi throat, which can drawNO into the vent flow like a carburetor draws liquid/gas into an intakeair stream in a correct proportion. Thus, increased vent flow canincrease NO flow proportionally. In some embodiments, a bluff bodyobstruction can be inserted into a ventilator circuit, and flow acrossthe obstruction can create a low pressure wake which draws in NO. Insome embodiments, a flow restriction can be included after the plasma tokeep the pressure high in the spark chamber and increase NO output. Thisflow restriction can be useful for altitude compensation. In someembodiments, a flow restriction can be included at the end of thescavenger so that NO-containing gas is at higher pressure and can flowinto the vent flow at all times, including when the vent flow is at highpressure. In some embodiments, a feedback control on the pump can beused to maintain constant pressure in a spark chamber. This can accountfor variance in ambient pressure and pre-scavenger resistance. Sparkchamber pressure can also be used as an input into the NO generationcontrol algorithm. In some embodiments, a variable orifice can beincluded after the plasma to increase pressure within a spark chamber,and the orifice can control NO flow during an inspiratory pulse.

Higher elevations have lower ambient pressure, and lower air density.Lower air density can decrease the electrical resistance between theelectrodes and plasma breakdown across the electrode gap can occur at alower voltage. With less air present and less voltage, there is adecrease in NO production at higher elevations measuring roughly 20%less at an elevation of 18,000 feet. In some embodiments, a variableflow restriction can be placed downstream of the plasma to create aback-pressure within the plasma chamber to increase absolute airpressure within the plasma chamber and NO production efficiency. Theorifice can be controlled in a closed-loop fashion with plasma chamberpressure as the input and a target pressure of atmospheric pressure atsea level.

In some embodiments, an NO generation module can be provided thatincludes a manual ventilation mode (a bag mode) that allows the moduleto support the use of respiratory bag or other manual ventilationmechanism to ventilate a patient. Ventilators do not always supportpatient bagging. In some embodiments, a ventilator user interface canprovide a user with a bag button that can toggle to bag mode operation,and the ventilator can communicate with the NO generation module andnotify the NO generation module that a user has selected bag mode. Insome embodiments, a bag button can be located on the NO generationmodule. Once the bag button is pressed, the system can automaticallyredirect product gases from the ventilator circuit to the manual baggingcircuit. In some embodiments, the NO module can measure flow of bag gasas it flows from an inlet to an outlet through the NO module. In someembodiments, the ventilator can provide air for bag flow to the NOmodule and a combination of NO and air can travel through an outlet inthe NO module and into the bag. In some embodiments, the NO generationmodule could have at least two outlets: 1 for a ventilator circuit and 1for a bag output. In some embodiments, a source for air/gas for the bagcan come from a cylinder or a wall outlet and can flow through an inletin a module enclosure. Within the module, the flow of the source air canbe measured and a proportional amount of NO can be added to the flowprior to exiting through a bag flow outlet. In some embodiments, sourceair/gas for a bag can be delivered to the module from the ventilator.

FIG. 117 illustrates an exemplary NO delivery system including an NOgeneration module 1460 removably coupled and inserted into a ventilator1462. The NO generation module includes a nipple 1464 to allow a bag tobe attached thereto, and air/O₂ is sourced from the ventilator. The NOgeneration module is configured to generate NO and pumps the NO-infusedair to either the bag nipple or to a ventilator output 1466.

The ventilator can have various additional features. NO weaning can bebased on ventilator weaning or on SpO₂, which can be measured by theventilator. By integrating the NO generation module, the ventilator canknow how much the O₂ concentration is diluted by the addition of NO andcan display the information accordingly. This can eliminate the need fora duplicate sensor that samples from the inspiratory limb. Theventilator can determine final concentration using a variety oftechniques, including measuring O₂ levels of the inspiratory gas post-NOintroduction, or using an algorithm or look-up table to determine O₂level based on NO volume added and initial O₂ level. This can eliminatesome user confusion by providing a single O₂ measurement, rather thanupstream and downstream measurements.

A multiple gas monitor or module can also be used with the system thatcan measure various gas levels, including but not limited to etCO₂, O₂,NO and NO₂. In some embodiments, a single gas sample line can be usedsuch that less volume is removed from the ventilator circuit. It canutilize the same sampling gas flow circuit (pump, filter, water trap)and a common processor, power supply, and/or user interface. The gasmonitor can be a stand-alone monitor device (such as a sensor module asdescribed in more detail below) or can be part of the ventilator. Insome embodiments, this could be a module that is either built within theventilator or can be installed and removed into a slot on the exteriorof a ventilator. As a removable module, it can share power, alarms, userinputs, treatment settings, and other features with the primary piece ofequipment, such as the ventilator.

FIG. 118 illustrates an exemplary embodiment of an NO generation module1470 embedded inside a ventilator 1472. The module can be removable fromthe ventilator or can be permanently embedded therein. The NO generationmodule is configured to generate NO and deliver the NO-infused air to aventilator output. In some embodiments, the O₂ level can be measured atthe output of the ventilator to determine if the gas includes the propergas levels required, such as O₂ gas.

FIG. 119 illustrates an exemplary embodiment of an NO generation module1480 removably coupled to a ventilator 1482. The external NO generationmodule adds NO to air entering the ventilator. The ventilator providesthe NO generation module with a target NO concentration. The NOgeneration module uses an air source 1484, such as ambient/atmosphericair, to generate NO in a product gas and pump the NO-infused product gasto the ventilator.

FIG. 120 illustrates an exemplary embodiment of an external NOgeneration module 1490 removably coupled to a ventilator 1492. The NOgeneration module may be removably attached to the wall of the clinicwith a pneumatic connection to the ventilator for NO delivery. Theventilator provides the NO generation module with a target NOconcentration. The NO generation module is configured to generate NO andto deliver NO to the ventilator, which also has its own air source 1494and O₂ source 1496, as shown in FIG. 120.

FIG. 121 illustrates an exemplary embodiment of an NO generation module1500 removably inserted into a ventilator 1502, for example into amodule dock or bay. The NO generation module uses ambient air as thereactant gas to generate NO and delivers the NO to the ventilator usingan internal pneumatic fitting and tube or other mechanism internal tothe ventilator.

FIG. 122 illustrates an exemplary embodiment of an NO generator 1510removably inserted into a ventilator 1512, for example into a moduledock or bay. The NO generation module uses ambient compressed air togenerate NO and delivers the NO to an output 1514 of the ventilator 1512using a tube 1516 or other mechanism external to the NO generationmodule and the ventilator. Thus, rather than an internal connectionbetween the NO generation module and the ventilator, an externalconnection can be used to deliver NO from the module to the ventilator.In some embodiments, the NO generation module and the ventilator haveseparate air sources. In some embodiments, the NO generation moduleincludes the NO₂ scavenger.

An NO generation module can also be used with an anaesthesia machine. NOwithin an anaesthesia circuit can accumulate, and gas analysis sensordata can be used to control NO production. Gas analysis sensormeasurements can be in the inspiratory limb and/or expiratory limb. IfNO production is modified by feedback or monitoring of NO levels at oneor more locations in a ventilation circuit, in some embodiments two ormore NO sensors can be used to provide redundancy and/or fault tolerancefor the control system. A pre-existing scavenger material in theanaesthesia circuit can be used to remove NO₂. NO production can becontrolled based on exhaled NO levels as exhaled NO can be an indicationof how much NO is within the patient. Thus, NO production could bemodulated to control the level of exhaled NO.

FIG. 123 illustrates an exemplary embodiment of an NO generation module1520 with an anaesthesia machine 1522. The anaesthesia machine 1522includes an NO generation module (either removably coupled thereto orembedded within the machine) and a scavenger 1524 that can be unitarywith the NO generation module or separate therefrom as long as thescavenger can be removed and replaced when necessary. The anaesthesiamachine 1522 and the NO generation module 1520 provide air that includesNO and anaesthesia to the patient. The exhaled gases from the patientcan be passed to a scavenger reservoir 1526 and its output can go backinto the anaesthesia machine. Sample gas 1528 can be sampled from theinspiratory limb before that gas reaches the patient. In someembodiments, the sample gas is used by the anaesthesia machine tomeasure concentration of various gases. In some embodiments, that samplegas can be tested by a sensor module or by sensors in the NO generationmodule. Also shown are optional blood oxygen saturation level (SpO₂)input and pulmonary artery pressure (PaP) input 1529 to the anesthesiamachine as control inputs for setting NO levels.

Using an NO generation module with an anaesthesia machine is achievedwith a similar approach as the ventilator with an NO generation modulebeing able to share power, an air source, a user display, alarmhardware, treatment control software, and other features. Anaesthesiamachines are typically operated in a closed loop so that anaesthesiagases are conserved and not dispersed into the room. The scavengermaterial of an anaesthesia machine can be used to absorb patient-exhaledCO₂ in the circuit. The same material, for example soda lime, can beused to scavenge NO₂ from the circuit, but NO levels would build up. Insome embodiments, to prevent NO build-up, anaesthesia can be provided inan open-loop format where exhaust gases are vented to the outside, to ahouse vacuum, or deactivated with a charcoal filter or other means. Insome embodiments, to prevent NO build-up, the module and/or anaesthesiamachine can measure NO levels in the closed circuit and adjust NOproduction levels accordingly to achieve the target treatment level. Theanaesthesiologist can benefit from having NO and NO₂ levels present intheir standard gas monitor equipment. In some embodiments, thesemonitors measure gases including CO₂, O₂, NO₂, Halothane, Isoflurane,Sevoflurane, Desflurane and Enflurane. The gas monitor would communicatewith either the treatment control software in the anaesthesia machine orthe NO generation module to control NO production levels.

NO generation modules can also be used in conjunction with C-PAPmachines. C-PAP machines are used at night to prevent sleep apnea. Insome embodiments, the addition of NO can improve blood oxygenation morethan oxygen and C-PAP alone. An NO generation module can be integratedinto the enclosure of a C-PAP machine, or can be a module thatoptionally removably inserts into the C-PAP machine or removably couplesthereto. Similar synergies exist with a C-PAP machine, namely power,user interface, air source, alarm hardware.

FIG. 124 illustrates an exemplary embodiment of a C-PAP machine 1530with an integrated NO generation module 1532. The NO generation modulecan share air supply, a controller 1534, power, and an enclosure withthe C-PAP machine hardware. In some embodiments, the NO generationmodule 132 can include its own air pump 1536. In some embodiments, anair pump can be shared between the C-PAP machine and the NO generationmodule. FIG. 125 illustrates an exemplary embodiment of a C-PAP 1540 andan NO generation module 1542 in which all of the C-PAP flow travelsthrough the NO generation module, which can allow for the dilution ofthe NO concentration to reduce NO₂ production. In some embodiments, theC-PAP device operates with a shared air pump 1544 for NO generation andthe C-PAP. The NO₂ scavenger 1546 can be in the form of a removablescavenger cartridge or a reservoir that can support scavenger materialreplacement. The C-PAP machines can include a treatment controller 1548that can be in communication with a user interface 1550 to allow a userto control the machine. In some embodiments, the treatment controller isconfigured to control the air pump and the generation of NO using the NOgeneration module.

NO generation modules can be used with or combined with oxygen tanks orconcentrators to improve blood oxygenation. FIG. 126 shows how an NOmodule can be used in series with an O₂ source, in parallel with an O₂source, or embedded in an O₂ source. FIG. 126 shows separate NO and O₂lines going to the patient. Depending on the NO concentration, transittime, and oxygen levels, a single lumen can be used to deliver O₂ and NOas well.

O₂ delivery to a patient may be constant flow or pulsed. When O₂ flow isthrough the NO module, the flow rate of O₂ can be sensed by the NOmodule so that NO flow is scaled appropriately. During pulsed O₂delivery, the NO module can sense pressure, flow, or sound variations inthe O₂ flow in order to synchronize NO delivery with O₂ pulses.Alternatively, the NO concentration device can receive flow and timingdata directly from an O₂ source via wired or wireless means.

One benefit of using an NO generation module in series with an O₂ sourceis that the NO generation module can detect a no-oxygen-flow conditionand sound and alarm.

In another embodiment, an NO generation module shares resources with anO₂ Concentrator in a “piggy-back” configuration. In this embodiment, theNO device interfaces with the mobile concentrator or a stationarycentral oxygen delivery system to share battery power and AC powersupply power from the oxygen system to avoid duplication and sentriedcharging and discharging behaviour. In this configuration, breathsynchronization can be done with a wired or wireless signal from the O₂source to the NO generation device. The signal can be related to breathdetection, a flow rate, a pressure signal, a trigger signal, an acousticsignal, a temperature signal or other type of signal related torespiration.

The rate of NO conversion to NO₂ increases with increases in O₂concentration, NO concentration, and time. In some embodiments, the O₂source is up to 50 feet from the patient. If NO is added at the O₂source, the transit time can be lengthy, thereby increasing the amountof NO to NO₂ conversion prior to patient inspiration. To address thispotential for elevated NO₂ levels, a proximal scavenger unit near thepatient can be used. The proximal scavenger consists of a chemicalscavenger (typically soda lime) located near the patient. The scavengermay be in the form of a pendant at the base of the patient's neck, wherethe cannula bifurcates. In one embodiment, the scavenger materialpellets and/or coatings are within the lumen of the cannula tubing.

FIG. 127 depicts an oxygen concentrator 1560 with integral NO module.Ambient air is compressed by the oxygen concentrator prior to beingdirected to both the NO generation device and molecular sieve beds. Highconcentration O₂ is stored within the product tank prior to delivery tothe patient. The NO generation device receives treatment settinginformation and O₂ flow rate information from the O₂ concentrator. NO isgenerated in atmospheric air (20% O₂), however it is possible to sendair with higher concentrations of O₂ to the NO module for improved NOproduction efficiency (50/50 ratio of O₂ to N₂ is optimal).

NO generation modules can also be used in conjunction with anextracorporeal membrane oxygenator (ECMO). An NO generation module canbe added to an ECMO machine as a fully-embedded subcomponent or as anoptional module that can be removably inserted or removably coupledthereto. In some embodiments, using NO with ECMO can improve long termsurvival rates by protecting the kidney. An NO module can receive powerand/or treatment settings from the ECMO machine. In return, the NOgeneration module can provide NO and alarms. The two systems can sharevarious features, including but not limited to alarm hardware, userdisplay, a power supply, and an enclosure.

FIG. 128 illustrates an exemplary embodiment of an ECMO system 1570 withan embedded NO generation module 1572. In some embodiments, air can besourced from a house supply for NO generation and gas blending. In someembodiments, air for NO generation can be sourced from ambient,NO-containing air that passes from the NO generator through a scavenger1574 to a gas blender 1576 and on to a blood oxygenator 1578. As shownin FIG. 128, the NO generation module can share various components withthe ECMO system, including a user display 1580, a power supply 1582, atreatment controller 1584, an enclosure, an alarm system (not shown),and an air source. As shown in FIG. 128, an NO generation module cangenerate NO that can be passed through a scavenger to remove NO₂. Thescavenger can be a separate component or can be housed within the NOgeneration module such that the scavenger can be replaced whennecessary. The gas blender has a variety of inputs, including ambientair, O₂, CO₂, and the output from the NO generation module andscavenger. The output gas from the gas blender can be passed to a bloodoxygenator that can send this gas to a patient. The ECMO system can alsoinclude a treatment controller to allow a user to control the gas passedto the patient.

In order to integrate an NO generation device into a piece of capitalequipment, such as a ventilator, measurements of various gas levels,including NO and NO₂, can be needed. When using various respiratory oroxygen concentration-related devices, numerous sensors can be used formeasuring concentrations of a variety of gases or other substances. Asensor module can be used alone or in combination with an NO generationmodule to measure various levels of substances related to the NOgeneration module, the medical machine, and/or the patient. For example,gas analysis sensors, such as electrochemical sensors, can be used andcan have a finite service life and can be changed out periodically.

In some embodiments, the sensor module can include one or more standardinputs (for example, sample gas, power, sample gas pump commands, modecommands) and can return one or more outputs (for example, gasconcentrations of one or more gases, water trap level, sample gas flowrate, and/or alarm conditions). Alarm conditions can include but are notlimited to NO₂ high, water trap full, sample gas flow zero indicating aproblem with a sample line, such as a kinked sample line. In someembodiments, the sensor module can receive a single power input, such asa 12 VDC, to power the pump, sensors, and/or microprocessor. In someembodiments, the sensors can be digitized and provided as an output viaan I2C communication. In some embodiments, the sensor module can alsomonitor the water level in a water trap that is used to collect moisturefrom a gas sample. A water trap can be included as part of a sensormodule. Drying of a sample gas can be accomplished using a coalescingfilter, centripetal vortex, hydrophobic membrane, chemical desiccant, orother means. Depending on the sensor methodology, excessively dry samplegases can affect sensor performance. In some embodiments, to protectsample sensors from sample gas with inadequate humidity, a length ofNafion tubing can be included prior to the sensors to draw humidity fromthe ambient air into the sample.

One or more of the sensor outputs from the sensor module can bedigitized and delivered over an I2C bus, or equivalent (USB, RS232,etc.). By standardizing the inputs and outputs to the sensor module, theinternal components (for example, a pump, one or more gas sensors, oneor more water level sensors, and one or more valves) can be upgradedwithout affecting the remainder of the capital equipment (i.e. aventilator). By utilizing a sensor module, a user can also takeadvantage of improvements in sensing technology with the replacement ofa sensor module with upgraded components.

NO generation devices typically measure various gases, including NO, NO₂and O₂. By combining a plurality of sensors into a replaceable sensormodule, it ensures that sensors are installed in the proper locationssuch that calibration and measurement accuracy are not compromised. Thepneumatic connections from the sensor to a manifold can be made duringmanufacture of the module instead of by a user, thereby eliminating thepotential for a partially-installed sensor introducing a leak to thesystem. Leaks can be a problem as they can affect sensor readings bydecreasing the signal level and can introduce corrosive NO and NO₂ tothe interior of the sensor module and/or NO generation equipment, whichcan lead to electrical failure. Replacement schedules can be easier tomanage by a user because there is one replacement item (the entiresensor module) instead of individual sensors to be replaced.

By establishing a standard interface (for example, I2C communication)between the sensor module and capital equipment, internals to the sensorpack can be upgraded to take advantage of new sensor and/or pumptechnology without affecting the primary capital equipment.

In some embodiments, a pump that draws sample gas flow to the sensorscan be located within the sensor module. This enables the use of a lowercost pump that can be replaced with the sensors, rather than requiring along-term pump that is compatible for long term exposure to NO and NO₂.Including the sample pump within the sensor module allows the pump to beprogrammed to run at the correct speed for the sensors in the module.Furthermore, a sample gas pump within the sensor pack can be positionedbefore the sensors, thereby pushing air to the sensors with positivepressure, rather than subjecting the sensors to vacuum pressure. Thiscan help to maintain a sample pressure closer to atmospheric levels atthe location of the sensors, thereby preventing an excessive pressuredifferential between the sensor case and sensing element. It can alsoprevent introduction of ambient gases into the sample in the presence ofa leak, thereby diluting the sample concentration.

In some embodiments, the sensor module can include a water trap sensorfor determining water level within the sample gas water trap. In someembodiments, the water trap can use a capacitive means to measure fluidheight. It will be understood that other approaches can be used todetermine fluid height in the water trap, including but not limited toultrasonic, optical, floating magnet, and conductive techniques.

An exemplary embodiment of a sensor module 1590 is shown in FIG. 129. Insome embodiments, the sensor module 1590 includes one or more sensors1592 for measuring NO, NO₂, O₂, and/or CO₂. Sample gas can flow into thesensor module 1590 through an inlet 1594 and can be directed through awater trap 1596 such water can collect in the trap and the sample gascan pass therethrough. The sample gas can be directed to a gas pump 1598and a flow restriction device 1600 that can be configured to achieveconsistent flow of the sample gas through the sensor module. In someembodiments, the sensor module can also include a water trap and amechanism to control the humidity within the sensor module. For example,it can be a length of Nafion tubing 1602 to help convey humidity fromthe gas sample to the ambient surroundings or from the surroundings intothe sample to help ensure that the humidity levels are acceptable forthe gas sensors.

Additional sensors can also be included in the sensor module. Forexample, a sensor module can also include humidity, pressure and flowmeasurement sensors. One or more flow measurement sensors can be used toconfirm that sample gases are flowing and that the pump is functional.In some embodiments, one or more flow measurement sensors, and/or one ormore pressure sensors can be used to confirm that the sample line isproperly connected to the inspiratory circuit, without kink orobstruction, by comparing the prevailing flow resistance to a knowncharacteristic flow resistance. Other ways to ensure that the gases areflowing is to look at pump current, pump vibrations, sample linepressure/vacuum, and/or pump motor encoder. Sample gases can be pushedthrough the sensor module or pulled through the sensor module. In someembodiments, a low-cost pump can be included in the sensor module thatcan be replaced at the same frequency as the module. In someembodiments, the pump can be located before the sensors or after thesensors within the module. In some embodiments, the pump can be locatedin the capital equipment and not in the sensor module.

FIG. 130 illustrates an exemplary embodiment of the internal componentsof a sensor module 1610 where sample gases are pulled through the sensormodule. The sensor module can include an integrated water trap 1612 onthe left side (as shown in FIG. 130 by a black dashed quadrilateral).Sample gases can flow into the water trap 1612 and can be dried beforepassing through the dry air inlet 1614 and into Nafion tubing. TheNafion tubing adds humidity from the ambient environment in the eventthat dry calibration gases have been introduced to the sensor pack. TheNafion tubing connects to the manifold. Sample gases flow through thesensor manifold 1615 by three sensors 1616 (NO₂, NO and O₂) and on tothe gas outlet 1618. In some embodiments, the sample gas pump 1620 islocated outside the module, downstream of the gas outlet, and pullssample gases through the module.

FIG. 131 depicts an exemplary removable NO generation module 1630.Compressed air enters the module from the upper fitting. A removablescavenger cartridge 1632 is inserted into the NO exit of the module onthe bottom. The module receives power and treatment settings from theequipment the module is inserted into.

FIG. 132 depicts a combination NO generation and sensor gas analysismodule 1640. The module uses compressed air sourced through an upperconnection 1642. NO generation is powered by the equipment the module isinserted into. NO containing gas exits the bottom fitting through areplaceable NO₂ scavenger component 1644. Sample gases enter the upperright fitting 1646, where sample gases are dried in a water trap 1648.The reservoir of the water trap is removable for draining. This modulecontains NO and NO₂ sensors, however additional sensors could beincluded to analysis the same sample gas.

As explained above, NO generation can be associated with a patientmonitor. The NO generation capabilities can be integrated into a patientmonitor, or the patient monitor can be used with an NO generation moduleas described above.

The integration of an NO generation module or NO generation capabilitieswith any type of device, including but not limited to a patient monitoror a ventilator, can provide user benefits, including reduced cost dueto shared hardware including, but not limited to user display, alarmlights, speaker, back-up battery, power supply, nurse call hardware,hardware watchdog, ambient temperature and pressure sensors, etc. Acombined display enables a user to see the current patient vital signs,ventilation and hemodynamics in one location. This can save time andimproves the user's ability to assess relationships between the data.Furthermore, there are consistent and identical user interfaces foralarm and alarms settings as well as trend analysis and the ability toplot relationships between patient data are only a few aspects of thebenefits of an integrated solution. Since NO has a direct impact on thehemodynamic performance of the cardio pulmonary system, it can bebeneficial for the clinician to control the NO dose and see the effectsfrom one piece of equipment. Closed-loop control of NO delivery based onpatient status can be facilitated. Patient monitor values, including butnot limited to SpO₂, ETCO₂, respiratory rate, heart rate and otherfactors could serve as inputs into the NO generation algorithm.

In some embodiments, a patient monitor can be connected to a centralstation for remote viewing and alarming and to the hospital informationsystem, providing seamless data integration in the patient legal record.In some embodiment, a patient monitor can also be connected to an exportdata stream of a ventilator to integrate the ventilator settings, flowand airway pressure curves into NO treatment algorithms and/or thepatient treatment record.

Beside the benefit of data integration, an integrated device can reducespace and foot print which is highly desirable in a clinical setting.The space around a critically ill patient is occupied by monitoring andventilation equipment, including up to 16 infusion pumps, so anyreduction in foot print can make a clinical setting easier to work inand safer due a reduction in cables and tubes.

FIG. 133 illustrates an embodiment of a patient monitor 1650 withexpansion slots for use with various modules, including an NO module1652. The patient monitor is configured to receive AC power 1654 or DCpower from a wall. The patient monitor can include built in monitoringcapabilities 1656, including but not limited to heart rate, bloodpressure, respiration rate, SpO₂, etCO₂, ventilation pressure,ventilation flow, NO gas concentration, NO₂ gas concentration, and O₂gas concentration. Various connections to the patient for standardfeatures such as EKG and SpO₂ can be included (these connections are notshown). The monitor 1650 can include a display 1658 for observing alldata, trending and relationships between parameters. Time histories ofpatient parameters can also be shown on the display, while gauges forNO, NO₂ and O₂ can be shown (in some embodiments, at the bottom of thedisplay). NO, NO₂ and O₂ gas analysis sensors can be embedded in thepatient monitor, housed within a separate gas analysis device, or bewithin a module within the expansion dock (for example, as shown in FIG.134). The monitor can also provide a consistent alarm and display formatfor one or more patient parameters, making alarm priority and legibilitymore consistent across potential issues. Gas samples can be drawn fromthe patient inspiratory limb, typically just before the patient wyeconnector. In some embodiments, the patient monitor can include a pumpfor drawing sample gases and a water trap and/or Nafion tubing toprepare the gas sample. Exhaust sample gases are either released to theroom or connected to hospital vacuum.

FIG. 134 illustrates an embodiment of a patient monitor 1660 with an NOmodule 1664 and one or more gas analysis modules 1662. In someembodiments, inspiratory gas samples can be drawn into a gas analysismodule. The gas analysis module can include a water trap, length ofNafion tubing, NO sensor, O₂ sensor, NO₂, sensor, pressure sensor andtemperature sensor, and gas pump. The module box shown in FIG. 134 canbe located in a separate housing, as shown, or could be integrated intothe primary housing of the patient monitor.

In some embodiments, a patient monitor with an integrated NO modulesolution can be used in a catheterization laboratory where a patient ispretested for an upcoming open-heart surgery to determine if the patientis a responder to nitric oxide and can benefit from NO therapy duringsurgery and post-op in the ICU. In some embodiments of a catheterizationlaboratory implementation, there is no ventilator involved, only ahemodynamic monitor.

FIG. 135 illustrates an exemplary embodiment of a catheterizationlaboratory set-up utilizing a patient monitor 1670 with integrated NOgeneration. The patient monitor can receive patient parameters, such asetCO₂, respiration rate, EKG, and/or temperature. The patient monitorcan have an output of NO that is delivered directly to the patient.Delivery can occur through various means, including through a nasalcannula, ET tube, face mask or other means. NO delivery and patientresponse data can be collected synchronously and can be viewed andstored within the patient monitor. This can facilitate the ability toassess the patient's response to NO.

Electronic NO Tank

It is also possible for NO generation to be achieved using an electronicNO generation tank replacement device. This tank replacement device canused with any device that can utilize NO, including but not limited to aventilator, a CPAP machine, an anaesthesia device, and a patientmonitor. In some embodiments, the tank replacement device can be in theform of a standalone device that can generate NO to be added or blendedinto a medical gas stream or to be delivered directly to a patient in anundiluted form (for example, in the case of a test in a cath lab). Insome embodiments, the tank replacement device can produce a constantamount of NO at a constant flow rate. While the tank replacement devicecan include various features, in some embodiments the device can beconfigured to automatically adjust air flow (pump speed, air pressure,flow controller orifice diameter, flow valve duty cycle) and/or plasmaactivity (including but not limited to pulse width, pulse frequency,electrical current frequency, current level, plasma energy, primaryswitching voltage, and/or power) in order to maintain a target NOconcentration within the output of the device. The NO dose control canbe achieved using a variety of mechanisms, including software controls,electrical hardware controls, or mechanical controls.

In some embodiments, an NO generation tank replacement device caninclude a means to know the amount of NO to be generated. The NO dosecan be calculated based on data from a flow sensor in the medical gasair stream, or it can be from a user setting provided to the NOgenerator through various mechanisms, such as a touch screen interface,up-down buttons, a rotational knob, a linear potentiometer, or othermeans. The NO dose can also be calculated from flow data from a seconddevice, such as a patient monitor, ventilator, CPAP machine, or otherdevice that utilizes the NO.

The NO generation tank replacement device can include a means togenerate an air flow. Air flow can be generated from a device, such asblower, fan, bellows, or diaphragm pump. Air flow can come from acompressed gas source, where the NO generation device varies air flowautomatically with a flow controller, proportional valve, or the like.Air flow can come from a compressed gas source and be controlledmechanically with a valve that is adjusted by a user as part of settingthe dose. The proportional valve can be part of the NO generation deviceor located in the air supply before the NO generation device.

Various other components of the NO generation tank replacement devicecan include one or more spark gaps to generate a plasma for theformation of NO. The spark gap can include either continuous orintermittent arcing. A high voltage circuit can be used to generatesufficient voltage to break down air at the spark gap. A scavenger withNO₂-absorbing material can be provided to remove NO₂ from the NO flow.The scavenger can be in the NO flow before introduction into the mainflow, or the scavenger can be in the NO flow after introduction into themain flow.

In some embodiments, O₂ therapy can be administered to a patient at aconstant flow rate. When NO is added to a constant flow of medical gas(air, O₂, other), the NO delivery can be constant as well. Thistreatment scenario can be addressed by a very simple NO generationdevice that is not burdened by fast responding flow sensors andhigh-performance pumps and flow controllers, such as the NO generationtank replacement device.

FIG. 136 illustrates an exemplary embodiment of an electric NOgeneration tank 1680. Electrical power 1682 can be supplied from eitheran AC or DC source. In some embodiments, air can be sourced from ambientair through air inlets 1684 in the housing. NO can be generated withinthe unit and can be passed through a removable NO₂ scavenger 1686 at thedevice outlet 1688. Various user adjustment devices can be provided. Forexample, air flow level 1690 and NO dose adjustments 1692 can beprovided for a user to adjust settings of the NO generation tank.

FIG. 137 illustrates an exemplary embodiment of an internal structure ofthe electric NO generation tank 1680 of FIG. 136. In some embodiments,air can be sourced from the environment and passes through a filter 1694and pump 1696. Air leaves the pump and flows through a plasma chamber1698. The plasma generator is controlled by a controller 1700, forexample a CPU, which receives user dose and flow settings and transmitsthem to the plasma generator. The plasma generator can be comprised of ahigh voltage circuit with electrodes. Air passes through the plasmagenerator, where part of the N₂ and O₂ in the air is converted to NO andNO₂. The air then passes through a scavenger 1702 where NO₂ is absorbedbut NO levels are left largely intact. A combination of NO and air exitsthe air tank.

FIG. 138 illustrates an exemplary embodiment of an electric NOgeneration tank 1710 that can be connected to a pressurized gas source1712. Typically, the incoming gas is air or another combination of N₂and O₂. In some embodiments, the pressurized air can pass through afilter 1714 (although this can be optional, depending on the purity ofthe air source) and through a variable orifice 1716. The variableorifice can be controlled by a controller 1718, such as a controllerCPU, however manual control of the orifice can also be achieved. Thevariable orifice can be used to control the amount of air that flowsthrough the plasma generator 1722, thereby controlling the amount of NOgenerated. Additional NO generation controls can also be used, includingby varying the plasma activity (energy, pulse width, electrical currentfrequency, current, primary switching voltage etc.). The output from theNO generator contains NO₂ (for example, 6% to 10% of the NO level whenan iridium electrode is used). The NO₂ can be scrubbed using a scavenger(for example, soda lime) as it exits the tank. The scavenger 1720, suchas soda lime, has a finite life so it is packed in a removable housingthat can be replaced periodically.

In some embodiments, the system can periodically search for the resonantfrequency within the high voltage circuit. This can be done when thesystem is powered on, at the beginning of a patient treatment, daily, orsome other frequency. Determining the resonant frequency of the circuitaccounts for variation in manufacturing, electrode gap (from wear andmanufacturing), and transformer variance. By operating at the resonantfrequency, the system can generate a spark with more energy, therebyincreasing NO production.

FIG. 139 illustrates an exemplary embodiment of an electric NOgeneration tank 1730 with a remote output. Air can be sourced from theenvironment through a grill 1732 or other opening in the enclosure ofthe tank. The air can be processed further by being passed through aHEPA filter. The HEPA filter can be included in the NO₂ scavengercartridge 1734. In some embodiments, NO can be introduced to a flow ofgases remote to the NO generation tank (for example, a ventilatorcircuit). A multiple lumen tube 1736, for example a three-lumen tube,can be used to deliver NO to the remote gas flow. The two remaininglumens are used to measure the flow in the remote gas flow using adifferential pressure method, where the pressure sensor(s) are locatedwithin the NO generation tank device. Remote flow measurement can alsobe done with remote sensors at the end of the NO delivery tube,requiring both pneumatic and electrical connections to be made at the NOgeneration tank.

FIG. 140 illustrates an exemplary embodiment of a combined scavenger andambient air filter 1740 (CSAAF), such as the one described in FIG. 139.The combined scavenger and ambient filter 1740 facilitates replacementfor the user. The CSAAF can be connected to the NO generation devicethrough three pneumatic connections: NO+NO₂+air in 1742, NO+air out1744, and filtered ambient air in 1746. Ambient air can pass through aHEPA filter in the inserted end of the CSAFF and into an internaldiameter, where it enters the internal pump. The external-facing end isfilled with scavenger material. NO₂-containing air enters a pneumaticfitting on one side of the scavenger housing. A partition 1748 withinthe housing ensures that gases pass through a sufficient path length toabsorb an acceptable amount of NO₂. A combination of NO and air exit theopposing pneumatic fitting and pass on to the NO outlet.

FIG. 141 illustrates an exemplary embodiment of an NO generation tankdevice 1750 having a single lumen output. The device shown can receivetreatment parameters, wirelessly or by any other means, from otherhospital equipment, such as a patient monitor or a ventilator. Exampletreatment parameters include but are not limited to patient respiratoryrate, patient tidal volume, patient minute volume, patient air flowrate, ventilator settings, ventilator flow rate, ventilator flowtrigger, SpO₂, pulmonary artery pressure, and target NO dose. The deviceuses this information to determine NO generation settings. The NOgeneration can be at a constant rate or vary with the patient treatmentdata (respiratory rate or ventilation rate for example). NO output ispumped down a tube 1752 to either the patient directly or indirectly viaanother medical gas stream.

FIG. 142 illustrates an exemplary embodiment of an NO generator 1760with a remote flow sensor. Flow can be measured by a flow sensor 1762that is external to the NO generator. The flow sensor input can comefrom a dedicated flow sensor located within the patient inspiratorylimb, or it can come from a ventilator, anaesthesia machine, CPAPmachine or other medical device that measures air flow. The combinationof NO and air exits the device through the scavenger component 1764. Aircan be sourced from a variety of sources, such as air from theenvironment, a separate compressed air source, or other O₂ andN₂-containing gas mixtures.

During NO therapy, exhaled gases from a patient may contain NO and NO2.These exhaled gases can be released into the surrounding environment,elevating NO2 levels and potentially risking the health of the patient,care personnel and other nearby people. In one embodiment, theexpiratory gases of a patient are scrubbed for NOx prior to release intothe environment. Scrubbing for NOx can be done by carbon, soda lime andother materials. I one embodiment, a scrubber cartridge is attached tothe exhaust port of a ventilator to remove NOx from patient expiratorygases. In one embodiment, a ventilator exhaust scrubber cartridge has analarm feature that warns the user when the cartridge useable life hasbeen exhausted. In one embodiment, an NO generation and delivery devicetracks the use of a ventilator exhaust scrubber and alerts the user whenreplacement is warranted. In some embodiments, the replacement scheduleis based on one or more of the following parameters: scrubber ratedservice life, elapsed time since the scrubber was installed, amount ofNOx molecules delivered to the patient since the scrubber was installed,or other parameters that are related to the usable life of scrubbermaterials.

Ventilator treatment involves delivering to a patient the inspiratorypulses associated with breathing in addition to a bias flow whichconstantly flows. Some ventilators do not readily present the bias flowinformation, which could affect drug dosing of NO and other drugsdelivered in the inspiratory airway. In one embodiment, an NO generationand delivery system presents to the user information on the ventilatorflow, as detected by the NO generation and delivery device including oneor more of: ventilator bias flow, peak airway pressure, minute volume,tidal volume, Inspiration to Expiration ratio, ventilator mode (volumecontrol vs. pressure control) and other parameters pertinent toventilation therapy. In one embodiment, an NO generation and deliverysystem provides alarms in the event that ventilator flows are outside ofan acceptable range.

In one embodiment, an NO delivery system measures NO and/or NO2concentration in the product gas before it is injected into a patientairway.

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entirety. It will beappreciated that several of the above-disclosed and other features andfunctions, or alternatives thereof, may be desirably combined into manyother different systems or application. Various alternatives,modifications, variations, or improvements therein may be subsequentlymade by those skilled in the art.

1. A nitric oxide generation system, comprising: one or more plasmachambers each including one or more electrodes configured to generate aproduct gas containing nitric oxide using a flow of a reactant gasthrough the one or more plasma chambers; a controller configured toregulate the amount of nitric oxide generated in the product gas by theone or more electrodes in the one or more plasma chambers using one ormore parameters as input to a control algorithm, at least one of the oneor more parameters being related to the flow rate of the reactant gasinto the one or more plasma chambers; a reactant gas source that isconfigured to provide instantaneous high pressure reactant gas to theone or more plasma chambers; a flow controller positioned between thereactant gas source and the one or more plasma chambers and configuredto provide a controlled continuous variable flow of the reactant gasfrom the reactant gas source based on a measurement associated with amedical gas into which the product gas flows; and one or more scavengerpaths configured to remove NO₂ from the product gas generated by the oneor more plasma chambers, wherein the concentration of NO in the combinedproduct gas and medical gas is a target value.
 2. The nitric oxidegeneration system of claim 1, wherein the measurement associated withthe medical gas is the flow rate of the medial gas such that the airflow of the reactant gas through the one or more plasma chambers isproportional to the flow rate of the medical gas.
 3. The nitric oxidegeneration system of claim 1, wherein the reactant gas source is in theform of a reservoir.
 4. The nitric oxide generation system of claim 1,wherein the reactant gas source is in the form of a pump.
 5. The nitricoxide generation system of claim 1, wherein the flow controller isselected from the group consisting of one or more proportional valves,one or more digital valves, and a combination of at least oneproportional valve and at least one digital valves.
 6. The nitric oxidegeneration system of claim 1, further comprising one or more filterspositioned to receive NO-enriched air from the one or more scavengerpaths and configured to filter the NO-enriched air.
 7. The nitric oxidegeneration system of claim 1, further comprising a digital signalprocessor that generates a continuous, customizable control AC waveformas an input to a high voltage circuit.
 8. The nitric oxide generationsystem of claim 7, wherein the digital signal processor is configured tocontrol the shape of the AC waveform by controlling its frequency andduty cycle.
 9. A nitric oxide generation system, comprising: one or moreplasma chambers each including one or more electrodes configured togenerate a product gas containing nitric oxide using a flow of areactant gas through the one or more plasma chambers; a controllerconfigured to regulate the amount of nitric oxide generated in theproduct gas by the one or more electrodes in the one or more plasmachambers using one or more parameters as input to a control algorithm,at least one of the one or more parameters being related to the flowrate of the reactant gas into the one or more plasma chambers; areactant gas source that is configured to provide instantaneous highpressure reactant gas to the one or more plasma chambers; and a flowcontroller positioned between the reactant gas source and the one ormore plasma chambers and configured to provide a controlled continuousvariable flow of the reactant gas from the reactant gas source based ona measurement associated with a medical gas into which the product gasflows, wherein the concentration of NO in the combined product gas andmedical gas is a target value.
 10. The nitric oxide generation system ofclaim 9, further comprising one or more scavenger paths configured toremove NO₂ from the product gas generated by the one or more plasmachambers.
 11. The nitric oxide generation system of claim 9, wherein thereactant gas source is in the form of a reservoir.
 12. The nitric oxidegeneration system of claim 9, wherein the reactant gas source is in theform of a pump.
 13. A nitric oxide generation system, comprising: one ormore plasma chambers each including one or more electrodes configured togenerate a product gas containing nitric oxide using a flow of areactant gas through the one or more plasma chambers; a controllerconfigured to control the amount of nitric oxide generated in theproduct gas by the one or more electrodes in the one or more plasmachambers based on a control algorithm with one or more input parametersby varying at least one or more of the flow rate of the reactant gasinto the one or more plasma chambers and a plasma power in the one ormore plasma chambers; a reactant gas source that is configured toprovide instantaneous high pressure reactant gas to the one or moreplasma chambers; a flow controller positioned between the reactant gassource and the one or more plasma chambers and configured to provide acontrolled continuous variable flow of the reactant gas from thereactant gas source based on a measurement associated with a medical gasinto which the product gas flows; and wherein the concentration of NO inthe combined product gas and medical gas is a target value.
 14. Thenitric oxide generation system of claim 13, wherein the controlalgorithm input parameters are selected from the group consisting ofconcomitant treatment parameters, patient parameters, ambientenvironment parameters, device parameters, and NO treatment parameters.15. The nitric oxide generation system of claim 14, wherein theconcomitant treatment parameters include flow, pressure, gastemperature, gas humidity information relating to one or more devicebeing used in conjunction with the NO generation system.
 16. The nitricoxide generation system of claim 14, wherein the patient parametersinclude inspiratory flow, SpO₂, breath detection, tidal volume, minutevolume, or expiratory NO₂.
 17. The nitric oxide generation system ofclaim 14, wherein the ambient environment parameters include ambienttemperature, ambient pressure, ambient humidity, ambient NO, or ambientNO₂.
 18. The nitric oxide generation system of claim 14, wherein thedevice parameters include plasma chamber pressure, plasma chamber flow,plasma chamber temperature, plasma chamber humidity, electrodetemperature, electrode type, or electrode gap.
 19. The nitric oxidegeneration system of claim 14, wherein the NO treatment parametersinclude target NO concentration, indicated NO concentration, orindicated NO₂ concentration.
 20. The nitric oxide generation system ofclaim 13, further comprising one or more scavenger paths configured toremove NO₂ from the product gas generated by the one or more plasmachambers.
 21. The nitric oxide generation system of claim 13, whereinthe reactant gas source is in the form of a reservoir.